Novel compounds as ror gamma modulators

ABSTRACT

The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , n, m, p and q are as defined herein, which are active as modulators of retinoid-related orphan receptor gamma t (RORγt). These compounds prevent, inhibit, or suppress the action of RORγt and are therefore useful in the treatment of RORγt mediated diseases, disorders, syndromes or conditions such as, e.g., pain, inflammation, COPD, asthma, rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, neurodegenerative diseases and cancer.

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional ApplicationNo. 2930/MUM/2015 filed on Aug. 3, 2015; which is hereby incorporated byreference in its entirety.

TECHNICAL FIELD

The present patent application is directed to novel compounds which maybe useful as retinoid-related orphan receptor gamma t (RORγt)modulators.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (RORs) are transcription factors whichbelong to the steroid hormone nuclear receptor super family. The RORfamily consists of three members, ROR alpha (RORα), ROR beta (RORβ) andROR gamma (RORγ), also known as NR1F1, NR1F2 and NR1F3 respectively (andeach encoded by a separate gene RORA, RORB and RORC, respectively). RORscontain four principal domains shared by the majority of nuclearreceptors: an N-terminal A/B domain, a DNA-binding domain, a hingedomain, and a ligand binding domain. Each ROR gene generates severalisoforms which differ only in their N-terminal A/B domain. Two isoformsof RORγ, RORγ1 and RORγt (also known as RORγ2) have been identified.

RORγt is a truncated form of RORγ, lacking the first N-terminal 21 aminoacids and is exclusively expressed in cells of the lymphoid lineage andembryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288,2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast toRORγ which is expressed in multiple tissues (heart, brain, kidney, lung,liver and muscle).

RORγt has been identified as a key regulator of Th17 celldifferentiation. Th17 cells are a subset of T helper cells which produceIL-17 and other proinflammatory cytokines and have been shown to havekey functions in several mouse autoimmune disease models includingexperimental autoimmune encephalomyelitis (EAE) and collagen-inducedarthritis (CIA). In addition, Th17 cells have also been associated inthe pathology of a variety of human inflammatory and autoimmunedisorders including multiple sclerosis, rheumatoid arthritis, psoriasis,Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009,7:e003; Manel et al., Nat. Immunol., 2008, 9, 641-649). The pathogenesisof chronic autoimmune diseases including multiple sclerosis andrheumatoid arthritis arises from the break in tolerance towardsself-antigens and the development of auto-aggressive effector T cellsinfiltrating the target tissues. Studies have shown that Th17 cells areone of the important drivers of the inflammatory process intissue-specific autoimmunity (Steinman et al., J. Exp. Med., 2008, 205:1517-1522; Leung et al., Cell. Mol. Immunol., 2010 7: 182-189). Th17cells are activated during the disease process and are responsible forrecruiting other inflammatory cell types, especially neutrophils, tomediate pathology in the target tissues (Kom et al., Annu. Rev.Immunol., 2009, 27:485-517) and RORγt has been shown to play a criticalrole in the pathogenic responses of Th17 cells (Ivanov et al., Cell,2006 126: 1121-1133). RORγt deficient mice have shown no Th17 cells andalso resulted in amelioration of EAE. The genetic disruption of RORγ ina mouse colitis model also prevented colitis development (Buonocore etal., Nature, 2010, 464: 1371-1375). The role of RORγt in thepathogenesis of autoimmune or inflammatory diseases has been welldocumented in the literature. (Jetten et al., Adv. Dev. Biol., 2006,16:313-355; Meier et al. Immunity, 2007, 26:643-654; Aloisi et al., Nat.Rev. Immunol., 2006, 6:205-217; Jager et al., J. Immunol., 2009,183:7169-7177; Serafmi et al., Brain Pathol., 2004, 14: 164-174;Magliozzi et al., Brain, 2007, 130: 1089-1104; Barnes et al., Nat. Rev.Immunol., 2008, 8: 183-192).

In addition, RORγt is also shown to play a crucial role in othernon-Th17 cells, such as mast cells (Hueber et al., J Immunol., 2010,184: 3336-3340). RORγt expression and secretion of Th17-type ofcytokines has also been reported in NK T-cells (Eberl et al., Nat.Immunol., 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat.Immunol., 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol.,2009, 123: 1004-1011), suggesting an important function for RORγt inthese cells.

PCT Publication Nos. WO 2012/139775, WO 2012/027965, WO 2012/028100, WO2012/100732, WO 2012/100734, WO2012/064744, WO 2013/171729 and WO2015/008234 disclose heterocyclic compounds which are modulators ofretinoid-related orphan receptor gamma (RORγ) receptor activity.

In view of the above, a need exists for new therapeutic agents thatmodulate the activity of RORγt and thus will provide new methods fortreating diseases or conditions associated with the modulation of RORγt.

The present application is directed to compounds that are modulators ofthe RORγt receptor.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a compound of formula(I)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof,wherein

Ring A is selected from

Ring B is selected from C₃₋₆cycloalkyl, C₆₋₁₄aryl, 3-15 memberedheterocyclyl and 5 to 14 membered heteroaryl;

L is absent or is _(y)*-X—(CR^(x)R^(y))_(t)-*_(z); X is selected from O,NR^(x1) and

each of x, y and z represents a point of attachment;

R¹ is selected from hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

each occurrence of R² is independently selected from cyano, halogen,hydroxyl, C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C(O)C₁₋₈alkyl, C₃₋₆cycloalkyl,C(O)C₃₋₆cycloalkyl and 3 to 15 membered heterocyclic ring; eachoccurrence of R³ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

each occurrence of R⁴ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

each occurrence of R⁵ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

R^(a) and R^(b), which may be the same or different, are eachindependently selected from hydrogen and C₁₋₈alkyl;

R^(x) and R^(y) which may be the same or different, are eachindependently selected from hydrogen, C₁₋₈alkyl and hydroxyC₁₋₈alkyl; orR^(x) and R^(y) together with the carbon atom to which they areattached, form a 3 to 6 membered cycloalkyl ring;

R^(x1) is selected from hydrogen or C₁₋₈alkyl;

‘n’ is 0, 1, 2 or 3;

‘m’ is 0, 1 or 2;

‘p’ is 0, 1 or 2;

‘q’ is 0, 1, 2 or 3 and

‘t’ is 0, 1, 2 or 3.

The compounds of formula (I) may involve one or more embodiments.Embodiments of formula (I) include compounds of formula (II) and formula(III) as described hereinafter. It is to be understood that theembodiments below are illustrative of the present invention and are notintended to limit the claims to the specific embodiments exemplified. Itis also to be understood that the embodiments defined herein may be usedindependently or in conjunction with any definition and any otherembodiment defined herein. Thus the invention contemplates all possiblecombinations and permutations of the various independently describedembodiments. For example, the invention provides compounds of formula(I) as defined above wherein L is absent (according to an embodimentdefined below), R¹ is hydroxyl, methyl or methoxy (according to anotherembodiment defined below) and ‘p’ is 0 (according to yet anotherembodiment defined below).

According to one embodiment, specifically provided are compounds offormula (I), in which ring B is C₃₋₆cycloalkyl (e.g. cyclohexyl),C₆₋₁₄aryl (e.g. phenyl), 3-15 membered heterocyclyl (e.g.6-oxo-1,6-dihydropyridinyl, piperidinyl, piperazinyl or morpholinyl) or5 to 14 membered heteroaryl (e.g. isoxazolyl, pyrazolyl, thiazolyl,pyridinyl or pyrimidinyl).

According to another embodiment, specifically provided are compounds offormula (I), in which ring B is cyclohexyl, phenyl,6-oxo-1,6-dihydropyridinyl, piperidinyl, piperazinyl, morpholinyl,isoxazolyl, pyrazolyl, thiazolyl, pyridinyl or pyrimidinyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is absent.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is _(y)*-X—(CR^(x)R^(y))_(t)-*_(z) and ‘t’ is0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is _(y)*-X—(CR^(x)R^(y))_(t)-*_(z) and ‘t’is 1. In this embodiment, R^(x) is hydrogen and R^(y) is hydrogen,methyl or hydroxymethyl or R^(x) and R^(y) together form a cyclopropylring.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is _(y)*-X—(CR^(x)R^(y))_(t)-*_(z) and ‘t’ is2. In this embodiment, R^(x) and R^(y) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which L is

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R¹ is hydroxyl, C₁₋₈alkyl (e.g. methyl) orC₁₋₈alkoxy (e.g. methoxy).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R¹ is hydroxyl, methyl or methoxy.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each R² is cyano, halogen (e.g. F or Cl),C₁₋₈alkyl (e.g. methyl or ethyl), C₁₋₈alkoxy (e.g. methoxy),C₁₋₈alkoxyC₁₋₈alkyl (e.g. methoxyethyl), haloC₁₋₈alkyl (e.g.trifluoromethyl), C₃₋₆cycloalkyl (e.g. cyclopropyl), C(O)C₁₋₈alkyl (e.g.C(O)methyl), C(O)C₃₋₆cycloalkyl (e.g. C(O)cyclopropyl) or 3 to 15membered heterocyclic ring (e.g. oxetan-3-yl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each R² is cyano, F, Cl, methyl, ethyl,methoxy, methoxyethyl, trifluoromethyl, cyclopropyl, C(O)methyl,C(O)cyclopropyl or oxetan-3-yl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in each which R² is cyano, F, Cl, methyl, ethyl,methoxy, methoxyethyl, trifluoromethyl, cyclopropyl, C(O)methyl,C(O)cyclopropyl or oxetan-3-yl and ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each R³ is C₁₋₈alkyl (e.g. methyl or tert.butyl) or haloC₁₋₈alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which each R³ is methyl, tert-butyl ortrifluoromethyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R³ is methyl, tert-butyl or trifluoromethyl and‘m’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R⁴ is halogen (e.g. F or Cl).

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R⁴ is F.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R⁴ is F and p is 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (I), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or methyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R^(a) is hydrogen and R^(b) is C₁₋₈alkyl (e.g.methyl).

According to yet another embodiment specifically provided are compoundsof formula (I), in which R^(a) is hydrogen and R^(b) is methyl.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R¹ is methyl; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R¹ is methoxy; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (I), in which R¹ is hydroxyl; R^(a) is hydrogen and R^(b) ismethyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2-cyclopropylphenyl, 2,4-dichlorophenyl,2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl,2-chloro-4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,3,5-dimethylisoxazol-4-yl, 1-methyl-1H-pyrazol-4-yl,4-methylthiazol-5-yl, pyridin-4-yl or pyrimidin-5-yl.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘m’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘p’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which ‘q’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

Ring A is

Ring B is cyclohexyl, phenyl, 6-oxo-1,6-dihydropyridinyl, piperidinyl,piperazinyl, morpholinyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl orpyrimidinyl;

L is absent or is

R¹ is hydroxyl, methyl or methoxy;

R² is cyano, F, Cl, methyl, ethyl, methoxy, methoxyethyl,trifluoromethyl, cyclopropyl, C(O)methyl, C(O)cyclopropyl oroxetan-3-yl;

R³ is methyl, tert. butyl or trifluoromethyl;

R⁴ is F;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl;

‘n’ is 0, 1 or 2;

‘m’ is 0 or 1;

‘p’ is 0 or 1; and

‘q’ is 0.

According to yet another embodiment, specifically provided are compoundsof formula (I), in which

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2-cyclopropylphenyl, 2,4-dichlorophenyl,2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl,2-chloro-4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,3,5-dimethylisoxazol-4-yl, 1-methyl-1H-pyrazol-4-yl,4-methylthiazol-5-yl, pyridin-4-yl or pyrimidin-5-yl;

L is absent or is

R¹ is hydroxyl, methyl or methoxy;

R⁴ is F;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl;

‘p’ is 0 or 1; and

‘q’ is 0.

According to an embodiment, specifically provided are compounds offormula (I) with an IC₅₀ value of less than 1000 nM, preferably lessthan 500 nM, more preferably less than 100 nM, with respect to RORγtactivity.

Further embodiments relating to groups ring A, ring B, L, R¹, R², R³,R⁴, R⁵, R^(a), R^(b), n, m, p and q (and groups defined therein) aredescribed hereinafter in relation to the compounds of formula (II), orcompounds of Formula (III). It is to be understood that theseembodiments are not limited to use in conjunction with formula (II) or(III), but apply independently and individually to the compounds offormula (I). For example, in an embodiment described hereinafter, theinvention specifically provides compounds of formula (II) or (III) inwhich ‘m’ is 0 or 1 and consequently there is also provided a compoundof formula (I) in which ‘m’ is 0 or 1.

The invention also provides a compound of formula (II), which is anembodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (II)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein

Ring A is selected from

Ring B is selected from C₃₋₆cycloalkyl, C₆₋₁₄aryl, 3-15 memberedheterocyclyl and 5 to 14 membered heteroaryl;

each of x and y represents a point of attachment;

R¹ is selected from hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

each occurrence of R² is independently selected from cyano, halogen,hydroxyl, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C(O)C₁₋₈alkyl, C₃₋₆cycloalkyl,C(O)C₃₋₆cycloalkyl and 3 to 15 membered heterocyclic ring; eachoccurrence of R³ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

each occurrence of R⁴ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

R^(a) and R^(b), which may be same or different, are each independentlyselected from hydrogen and C₁₋₈alkyl;

‘n’ is 0, 1, 2 or 3;

‘m’ is 0, 1 or 2; and

‘p’ is 0, 1 or 2.

The compounds of formula (II) may involve one or more embodiments. It isto be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition, any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (II) as defined above wherein R¹ ishydroxyl, methyl or methoxy (according to an embodiment defined below),R^(a) is hydrogen (according to another embodiment defined below) and‘m’ is 0 or 1 (according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (II), in which ring B is C₆₋₁₄aryl (e.g. phenyl), 3-15 memberedheterocyclyl (e.g. 6-oxo-1,6-dihydropyridinyl, piperidinyl, piperazinylor morpholinyl) or 5 to 14 membered heteroaryl (e.g. pyrazolyl,pyridinyl or pyrimidinyl).

According to another embodiment, specifically provided are compounds offormula (II), in which ring B is phenyl, 6-oxo-1,6-dihydropyridin-3-yl,piperidinyl, piperazinyl, morpholinyl, pyrazolyl, pyridinyl orpyrimidinyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which R¹ is hydroxyl, C₁₋₈alkyl (e.g. methyl) orC₁₋₈alkoxy (e.g. methoxy).

According to yet another embodiment specifically provided are compoundsof formula (II), in which R¹ is hydroxyl, methyl or methoxy.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each R² is cyano, halogen (e.g. F or Cl),C₁₋₈alkyl (e.g. methyl or ethyl), C₁₋₈alkoxy (e.g. methoxy),C₁₋₈alkoxyC₁₋₈alkyl (e.g. methoxyethyl), haloC₁₋₈alkyl (e.g.trifluoromethyl), C(O)C₁₋₈alkyl (e.g. C(O)methyl), C(O)C₃₋₆cycloalkyl(e.g. C(O)cyclopropyl) or 3 to 15 membered heterocyclic ring (e.g.oxetan-3-yl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each R² is cyano, F, Cl, methyl, ethyl,methoxy, methoxyethyl, trifluoromethyl, C(O)methyl, C(O)cyclopropyl oroxetan-3-yl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in each which R² is cyano, F, Cl, methyl, ethyl,methoxy, methoxyethyl, trifluoromethyl, C(O)methyl, C(O)cyclopropyl oroxetan-3-yl, and ‘n’ is 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each R³ is C₁₋₈alkyl (e.g. methyl ortert-butyl) or haloC₁₋₈alkyl (e.g. trifluoromethyl).

According to yet another embodiment, specifically provided are compoundsof formula (II), in which each R³ is methyl, tert-butyl ortrifluoromethyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which R³ is methyl, tert-butyl or trifluoromethyland ‘m’ is 1.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R⁴ is halogen (e.g. F or Cl).

According to yet another embodiment specifically provided are compoundsof formula (II), in which R⁴ is F.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R⁴ is F and ‘p’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (II), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or methyl.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which R^(a) is hydrogen and R^(b) is C₁₋₈alkyl (e.g.methyl).

According to yet another embodiment specifically provided are compoundsof formula (II), in which R^(a) is hydrogen and R^(b) is methyl.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R¹ is methyl; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R¹ is methoxy; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (II), in which R¹ is hydroxyl; R^(a) is hydrogen and R^(b) ismethyl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,1-methyl-1H-pyrazol-4-yl, pyridin-4-yl or pyrimidin-5-yl.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘m’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which ‘p’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

Ring A

Ring B is phenyl, 6-oxo-1,6-dihydropyridinyl, piperidinyl, piperazinyl,morpholinyl, pyrazolyl, pyridinyl or pyrimidinyl;

R¹ is hydroxyl, methyl or methoxy;

R² is cyano, F, Cl, methyl, ethyl, methoxy, methoxyethyl,trifluoromethyl, C(O)methyl, C(O)cyclopropyl or oxetan-3-yl;

R³ is methyl, tert. butyl or trifluoromethyl;

R⁴ is F;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl;

‘n’ is 0, 1 or 2;

‘m’ is 0 or 1; and

‘p’ is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (II), in which

is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,1-methyl-1H-pyrazol-4-yl, pyridin-4-yl or pyrimidin-5-yl;

R¹ is hydroxyl, methyl or methoxy;

R⁴ is F;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl; and

‘p’ is 0 or 1.

According to an embodiment, specifically provided are compounds offormula (II) with an IC₅₀ value of less than 1000 nM, preferably lessthan 500 nM, more preferably less than 100 nM, with respect to RORγtactivity.

The invention also provides a compound of formula (III), which is anembodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (III)

or a tautomer thereof, a stereoisomer thereof or a pharmaceuticallyacceptable salt thereof, wherein

Ring B is selected from C₃₋₆cycloalkyl, C₆₋₁₄aryl, 3-15 memberedheterocyclyl and 5 to 14 membered heteroaryl;

X is selected from —O—, —NR^(x1)— and

R¹ is selected from hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy;

each occurrence of R² is independently selected from cyano, halogen,hydroxyl, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,haloC₁₋₈alkoxy, hydroxyC₁₋ ₈alkyl, C(O)C₁₋₈alkyl, C₃₋₆cycloalkyl,C(O)C₃₋₆cycloalkyl and 3 to 15 membered heterocyclic ring;

each occurrence of R⁴ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl;

R^(a) and R^(b), which may be the same or different, are eachindependently selected from hydrogen and C₁₋₈alkyl;

R^(x) and R^(y) which may be the same or different, are eachindependently selected from hydrogen, C₁₋₈alkyl and hydroxyC₁₋₈alkyl; orR^(x) and R^(y) together with the carbon atom to which they areattached, form a 3 to 6 membered cycloalkyl ring;

R^(x1) is selected from hydrogen or C₁₋₈alkyl;

‘n’ is 0, 1, 2 or 3;

‘p’ is 0, 1 or 2; and

‘t’ is 0, 1, 2 or 3.

The compounds of formula (III) may involve one or more embodiments. Itis to be understood that the embodiments below are illustrative of thepresent invention and are not intended to limit the claims to thespecific embodiments exemplified. It is also to be understood that theembodiments defined herein may be used independently or in conjunctionwith any definition, any other embodiment defined herein. Thus theinvention contemplates all possible combinations and permutations of thevarious independently described embodiments. For example, the inventionprovides compounds of formula (III) as defined above wherein X is O(according to an embodiment defined below), R¹ is hydroxyl or methyl(according to another embodiment defined below) and ‘n’ is 0, 1 or 2(according to yet another embodiment defined below).

According to one embodiment, specifically provided are compounds offormula (III), in which ring B is C₃₋₆cycloalkyl (e.g. cyclohexyl),C₆₋₁₄aryl (e.g. phenyl), 3-15 membered heterocyclyl (e.g. piperazinyl)or 5 to 14 membered heteroaryl (e.g. isoxazolyl or thiazolyl).

According to another embodiment, specifically provided are compounds offormula (III), in which ring B is cyclohexyl, phenyl, piperazinyl,isoxazolyl or thiazolyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which X is O.

According to yet another embodiment specifically provided are compoundsof formula (III), in which X is NR^(x1). In this embodiment NR^(x1) ishydrogen or methyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which X is —O—, —NH—, —N(CH₃)— or

According to yet another embodiment specifically provided are compoundsof formula (III), in which R^(x) is hydrogen; R^(y) is hydrogen; and tis 1 or 2.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R^(x) is hydrogen; R^(y) is methyl orhydroxymethyl; or R^(x) and R^(y) together with the carbon atom to whichthey are attached, form a cyclopropyl ring; and ‘t’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

wherein y and z represents point of attachment.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R¹ is hydroxyl or C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R¹ is hydroxyl or methyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each R² is halogen (e.g. F or Cl), C₁₋₈alkyl(e.g. methyl) or C₃₋₆cycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifically provided are compoundsof formula (III), in which each R² is F, Cl, methyl or cyclopropyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which each R² is F, Cl, methyl or cyclopropyl and‘n’ is 1 or 2.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R⁴ is halogen (e.g. F or Cl).

According to yet another embodiment specifically provided are compoundsof formula (III), in which R⁴ is F.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R⁴ is F and ‘p’ is 1.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or C₁₋₈alkyl (e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (III), in which one of R^(a) and R^(b) is hydrogen and theother is hydrogen or methyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R^(a) and R^(b) are hydrogen.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which R^(a) is hydrogen and R^(b) is C₁₋₈alkyl(e.g. methyl).

According to yet another embodiment specifically provided are compoundsof formula (III), in which R^(a) is hydrogen and R^(b) is methyl.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R¹ is methyl; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R¹ is methoxy; R^(a) is hydrogen and R^(b) ishydrogen.

According to yet another embodiment specifically provided are compoundsof formula (III), in which R¹ is hydroxyl; R^(a) is hydrogen and R^(b)is methyl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-cyclopropylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl,2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 3,5-dimethylisoxazol-4-ylor 4-methylthiazol-5-yl.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which ‘n’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

Ring B is cyclohexyl, phenyl, piperazinyl, isoxazolyl or thiazolyl;

X is —O—, —NH—, —N(CH₃)— or

R¹ is hydroxyl, methyl or methoxy;

R² is F, Cl, methyl or cyclopropyl;

R⁴ is F;

R^(a) is hydrogen; R^(b) is hydrogen or methyl;

R^(x) is hydrogen; R^(y) is hydrogen, methyl or hydroxymethyl; or R^(x)and R^(y) together form a cyclopropyl ring;

‘n’ is 0, 1 or 2;

‘p’ is 0 or 1; and

‘t’ is 0, 1 or 2.

According to yet another embodiment, specifically provided are compoundsof formula (III), in which

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-cyclopropylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl,2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 3,5-dimethylisoxazol-4-ylor 4-methylthiazol-5-yl;

y and z represents point of attachment;

R¹ is hydroxyl, methyl or methoxy;

R⁴ is F;

R^(a) is hydrogen;

R^(b) is hydrogen or methyl; and

‘p’ is 0 or 1.

According to an embodiment, specifically provided are compounds offormula (III) with an IC₅₀ value of less than 1000 nM, preferably lessthan 500 nM, more preferably less than 100 nM, with respect to RORγtactivity.

Compounds of the present invention include the compounds in Examples1-99. It should be understood that the formulas (I), (II) and (III)structurally encompasses all geometrical isomers, stereoisomers,enantiomers and diastereomers, N-oxides, and pharmaceutically acceptablesalts that may be contemplated from the chemical structure of the generadescribed herein.

The present application also provides a pharmaceutical composition thatincludes at least one compound described herein and at least onepharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition comprises a therapeutically effective amount of at least onecompound described herein. The compounds described herein may beassociated with a pharmaceutically acceptable excipient (such as acarrier or a diluent) or be diluted by a carrier, or enclosed within acarrier which can be in the form of a tablet, capsule, sachet, paper orother container.

The compounds and pharmaceutical compositions of the present inventionare useful for inhibiting the activity of RORγt. Thus, the presentinvention further provides a method of inhibiting RORγt in a subject inneed thereof by administering to the subject one or more compoundsdescribed herein in an amount effective to cause inhibition of suchreceptor.

In a further aspect, the present invention relates to a method oftreating a disease, disorder or condition modulated by RORγt, such as anautoimmune disease, inflammatory disease, respiratory disorder, pain andcancer comprising administering to a subject in need thereof a compoundaccording to any of the embodiments described herein.

In another aspect, the present invention relates to a method of treatinga disease, disorder or condition modulated by RORγt, such as chronicobstructive pulmonary disease (COPD), asthma, cough, pain, inflammatorypain, chronic pain, acute pain, arthritis, osteoarthritis, multiplesclerosis, rheumatoid arthritis, colitis, ulcerative colitis andinflammatory bowel disease, comprising administering to a subject inneed thereof a compound according to any of the embodiments describedherein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “halogen” or “halo” means fluorine (fluoro), chlorine(chloro), bromine (bromo), or iodine (iodo).

The term “alkyl” refers to a hydrocarbon chain radical that includessolely carbon and hydrogen atoms in the backbone, containing nounsaturation, having from one to eight carbon atoms (i.e. C₁₋₈alkyl),and which is attached to the rest of the molecule by a single bond, suchas, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). Theterm “C₁₋₈alkyl” refers to an alkyl chain having 1 to 8 carbon atoms.The term “C₁₋₄alkyl” refers to an alkyl chain having 1 to 4 carbonatoms.

Unless set forth or recited to the contrary, all alkyl groups describedor claimed herein may be straight chain or branched.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkageto the rest of the molecule (e.g. C₁₋₈₈ alkoxy). Representative examplesof such groups are —OCH₃ and —OC₂H₅. Unless set forth or recited to thecontrary, all alkoxy groups described or claimed herein may be straightchain or branched.

The term “haloalkyl” refers to at least one halo group (selected from F,Cl, Br or I), linked to an alkyl group as defined above (i.e.haloC₁₋₈alkyl). Examples of such haloalkyl groups include, but are notlimited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Theterm “haloC₁₋₈alkyl” refers to at least one halo group linked an alkylchain having 1 to 8 carbon atoms. Unless set forth or recited to thecontrary, all haloalkyl groups described herein may be straight chain orbranched.

The term “haloalkoxy” refers to an alkoxy group substituted with one ormore halogen atoms (i.e. haloC₁₋₈alkoxy). Examples of “haloalkoxy”include but are not limited to fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and1-bromoethoxy. Unless set forth or recited to the contrary, allhaloalkoxy groups described herein may be straight chain or branched.

The term “hydroxyC₁₋₈alkyl” refers to an C₁₋₈alkyl group as definedabove wherein one to three hydrogen atoms on different carbon atoms arereplaced by hydroxyl groups (i.e. hydroxyC₁₋₄alkyl). Examples ofhydroxyC₁₋₈alkyl moieties include, but are not limited to —CH₂OH and—C₂H₄OH.

The term “C₁₋₈alkoxyC₁₋₈alkyl” refers to an C₁₋₈alkyl group as definedabove wherein one to three hydrogen atoms on different carbon atoms arereplaced by alkoxy group as defined above. Examples ofC₁₋₈alkoxyC₁₋₈alkyl moieties include, but are not limited to —CH₂OCH₃and —C₂H₄OCH₃.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, (i.e. C₃₋₁₂cycloalkyl). Examplesof monocyclic cycloalkyl include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicycliccycloalkyl groups include, but are not limited to, perhydronapthyl,adamantyl and norbomyl groups, bridged cyclic groups or spirobicyclicgroups, e.g., spiro(4,4)non-2-yl. The term “C₃₋₆cycloalkyl” refers tothe cyclic ring having 3 to 6 carbon atoms. Examples of “C₃₋₆cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalhaving 3 to about 6 carbon atoms directly attached to an alkyl group(e.g. C₃₋₆cycloalkylC₁₋₈alkyl). The cycloalkylalkyl group may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure. Non-limitingexamples of such groups include cyclopropylmethyl, cyclobutylethyl, andcyclopentylethyl.

The term “aryl” refers to an aromatic radical having 6 to 14 carbonatoms (i.e. C₆₋₁₄aryl), including monocyclic, bicyclic and tricyclicaromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl,and biphenyl.

The term “heterocyclic ring” or “heterocyclyl” unless otherwisespecified refers to substituted or unsubstituted non-aromatic 3 to 15membered ring radical (i.e. 3 to 15 membered heterocyclyl) whichconsists of carbon atoms and from one to five hetero atoms selected fromnitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radicalmay be a mono-, bi- or tricyclic ring system, which may include fused,bridged or spiro ring systems, and the nitrogen, phosphorus, carbon,oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized; also, unless otherwiseconstrained by the definition the heterocyclic ring or heterocyclyl mayoptionally contain one or more olefinic bond(s). Examples of suchheterocyclic ring radicals include, but are not limited to azepinyl,azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl,dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl,isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,6-oxo-1,6-dihydropyridin-3-yl, octahydroindolyl, octahydroisoindolyl,perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl,phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl,tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl,thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide andthiamorpholinyl sulfone. The heterocyclic ring radical may be attachedto the main structure at any heteroatom or carbon atom that results inthe creation of a stable structure. Unless set forth or recited to thecontrary, all heterocyclyl groups described or claimed herein may besubstituted or unsubstituted.

The term “heteroaryl” unless otherwise specified refers to 5 to 14membered aromatic heterocyclic ring radical with one or moreheteroatom(s) independently selected from N, O or S (i.e. 5 to 14membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclicring system. The heteroaryl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure. Examples of such heteroaryl ring radicalsinclude, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl,indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl,oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl,benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl,isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl,purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl,acridinyl, phenazinyl and phthalazinyl.

The term “pharmaceutically acceptable salt” includes salts prepared frompharmaceutically acceptable bases or acids including inorganic ororganic bases and inorganic or organic acids. Examples of such saltsinclude, but are not limited to, acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate, diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Examples of salts derivedfrom inorganic bases include, but are not limited to, aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, mangamous, potassium, sodium, and zinc.

The term “treating” or “treatment” of a state, disorder or conditionincludes: (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

The compounds of formula (I), (II) or (III) may contain asymmetric orchiral centers, and, therefore, exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of formula(I), (II) or (III) as well as mixtures thereof, including racemicmixtures, form part of the present invention. In addition, the presentinvention embraces all geometric and positional isomers. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by the reactionwith an appropriate optically active compound (e.g., chiral auxiliarysuch as a chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolysing) the individualdiastereomers to the corresponding pure enantiomers. Enantiomers canalso be separated by use of chiral HPLC column. The chiral centers ofthe present invention can have the S or R configuration as defined bythe IUPAC 1974.

Pharmaceutical Compositions

The compounds of the invention are typically administered in the form ofa pharmaceutical composition. The pharmaceutical compositions describedherein comprise one or more compounds described herein and one or morepharmaceutically acceptable excipients. Typically, the pharmaceuticallyacceptable excipients are approved by regulatory authorities or aregenerally regarded as safe for human or animal use. The pharmaceuticallyacceptable excipients include, but are not limited to, carriers,diluents, glidants and lubricants, preservatives, buffering agents,chelating agents, polymers, gelling agents, viscosifying agents,solvents and the like.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil,gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate,sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,stearic acid, lower alkyl ethers of cellulose, silicic acid, fattyacids, fatty acid amines, fatty acid monoglycerides and diglycerides,fatty acid esters, and polyoxyethylene.

The pharmaceutical compositions described herein may also include one ormore pharmaceutically acceptable auxiliary agents, wetting agents,suspending agents, preserving agents, buffers, sweetening agents,flavouring agents, colorants or any combination of the foregoing.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofroute of administration, such as orally or parenterally. The route ofadministration may be any route which effectively transports the activecompound of the patent application to the appropriate or desired site ofaction.

Methods of Treatment

The compounds of the present invention are particularly useful becausethey inhibit the activity of retinoid-related orphan receptor gamma,particularly retinoid-related orphan receptor gamma t (RORγt), i.e.,they prevent, inhibit, or suppress the action of RORγt, and/or mayelicit a RORγt modulating effect. Compounds of the invention aretherefore useful in the treatment of those conditions in whichinhibition of ROR gamma activity, and particularly RORγt, is beneficial.

The compounds of the present patent application are modulators of RORγtand can be useful in the treatment of diseases or disorder mediated byRORγt. Accordingly, the compounds and the pharmaceutical compositions ofthis invention may be useful in the treatment of inflammatory, metabolicand autoimmune diseases mediated by RORγt.

The term “autoimmune diseases” will be understood by those skilled inthe art to refer to a condition that occurs when the immune systemmistakenly attacks and destroys healthy body tissue. An autoimmunedisorder may result in the destruction of one or more types of bodytissue, abnormal growth of an organ, and changes in organ function. Anautoimmune disorder may affect one or more organ or tissue types whichinclude, but are not limited to, blood vessels, connective tissues,endocrine glands such as the thyroid or pancreas, joints, muscles, redblood cells, and skin. Examples of autoimmune (or autoimmune-related)disorders include multiple sclerosis, arthritis, rheumatoid arthritis,psoriasis, Crohn's disease, gastrointestinal disorder, inflammatorybowel disease, irritable bowel syndrome, colitis, ulcerative colitis,Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratorydisorder, chronic obstructive pulmonary disease (COPD), asthma, type Idiabetes, neuromyelitis optica, Myasthenia Gavis, uveitis,Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, allergy,osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto'sthyroiditis, Pernicious anemia, Addison's disease, Systemic lupuserythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus,Myasthenia gravis, Reactive arthritis, Celiac disease—sprue(gluten-sensitive enteropathy), Graves's disease, thymopoiesis andLupus.

Compounds of the present patent application may also be useful in thetreatment of inflammation. The term “inflammation” will be understood bythose skilled in the art to include any condition characterized by alocalized or a systemic protective response, which may be elicited byphysical trauma, infection, chronic diseases, and/or chemical and/orphysiological reactions to external stimuli (e.g. as part of an allergicresponse). Any such response, which may serve to destroy, dilute orsequester both the injurious agent and the injured tissue, may bemanifest by, for example, heat, swelling, pain, redness, dilation ofblood vessels and/or increased blood flow, invasion of the affected areaby white.

The term “inflammation” is also understood to include any inflammatorydisease, disorder or condition per se, any condition that has aninflammatory component associated with it, and/or any conditioncharacterized by inflammation as a symptom, including inter alia acute,chronic, ulcerative, specific, allergic, infection by pathogens, immunereactions due to hypersensitivity, entering foreign bodies, physicalinjury, and necrotic inflammation, and other forms of inflammation knownto those skilled in the art. The term thus also includes, for thepurposes of this present patent application, inflammatory pain, paingenerally and/or fever.

The compounds of the present invention may be used for treatment ofarthritis, including, but are not limited to, rheumatoid arthritis,osteoarthritis, psoriatic arthritis, septic arthritis,spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) andother arthritic conditions.

The compounds of the present invention may be used for treatment ofrespiratory disorders including, but are not limited to, chronicobstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.

Other respiratory disorders include, but are not limited to, bronchitis,bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronicsinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis,tracheitis, epiglottitis, croup, chronic disease of tonsils andadenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess,rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterialpneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis,coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy,respiratory conditions due to chemical fumes, vapors and other externalagents, emphysema, pleurisy, pneumothorax, abscess of lung andmediastinum, pulmonary congestion and hypostasis, postinflammatorypulmonary fibrosis, other alveolar and parietoalveolar pneumonopathy,idiopathic fibrosing alveolitis, Hamman-Rich syndrome, atelectasis,ARDS, acute respiratory failure, and mediastinitis.

The compounds of the present invention may also be used for treatment ofpain conditions. The pain can be acute or chronic pain. Thus, thecompounds of the present invention may be used for treatment of e.g.,inflammatory pain, arthritic pain, neuropathic pain, post-operativepain, surgical pain, visceral pain, dental pain, premenstrual pain,central pain, cancer pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, viral, parasitic or bacterial infection,post-traumatic injury, or pain associated with irritable bowel syndrome.

The compounds of the present invention may further be used for treatmentof gastrointestinal disorder such as, but not limited to, irritablebowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis,biliary colic and other biliary disorders, renal colic,diarrhea-dominant IBS, and pain associated with gastrointestinaldistension.

In addition, the compounds of the present invention may be useful in thetreatment of cancer, and pain associated with cancer. Such cancersinclude, e.g., multiple myeloma and bone disease associated withmultiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia(AML), head and neck squamous cell carcinoma, hepatocellular carcinoma,gastric cancer, bladder carcinoma and colon cancer.

The compounds of the present invention may be useful in a treatment ofdisease, disorder, syndrome or condition selected from the groupconsisting of chronic obstructive pulmonary disease (COPD), asthma,cough, pain, inflammatory pain, chronic pain, acute pain, arthritis,osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis,ulcerative colitis and inflammatory bowel disease.

Any of the methods of treatment described herein comprise administeringan effective amount of a compound according to Formula (I), (II) or(III), or a pharmaceutically-acceptable salt thereof, to a subject(particularly a human) in need thereof.

The present inventions further relates to the use of the compoundsdescribed herein in the preparation of a medicament for the treatment ofdiseases mediated by RORγt.

The compounds of the invention are effective both in the therapeuticand/or prophylactic treatment of the above-mentioned conditions. For theabove-mentioned therapeutic uses the dosage administered may vary withthe compound employed, the mode of administration, the treatment desiredand the disorder.

The daily dosage of the compound of the invention administered may be inthe range from about 0.05 mg/kg to about 100 mg/kg.

General Methods of Preparation

The compounds, described herein, including those of general formula(Ia), (Ib) and (II), intermediates and specific examples are preparedthrough the synthetic methods as depicted in Schemes 1 to 14.Furthermore, in the following schemes, where specific acids, bases,reagents, coupling reagents, solvents, etc. are mentioned, it isunderstood that other suitable acids, bases, reagents, couplingreagents, solvents etc. may be used and are included within the scope ofthe present invention. The modifications to reaction conditions, forexample, temperature, duration of the reaction or combinations thereof,are envisioned as part of the present invention. The compounds obtainedusing the general reaction sequences may be of insufficient purity.These compounds can be purified using any of the methods forpurification of organic compounds known to persons skilled in the art,for example, crystallization or silica gel or alumina columnchromatography using different solvents in suitable ratios. All possiblegeometrical isomers and stereoisomers are envisioned within the scope ofthis invention.

The starting materials used herein are commercially available or wereprepared by methods known in the art to those of ordinary skill or bymethods disclosed herein. In general, the intermediates and compounds ofthe present invention can be prepared through the reaction schemes asfollows. In some cases the final product may be further modified, forexample, by manipulation of substituents. These manipulations mayinclude, but are not limited to, reduction, oxidation, alkylation,acylation, hydrolysis, and cleavage of protecting groups etc., byfollowing procedures known in the art of organic synthesis.

A general approach for the preparation of compounds of the formulae (Ia)and (Ib) (wherein ring A and ring B, L, R¹, R², R³, R⁴, R⁵, R^(b), ‘n’,‘m’, ‘p’ and ‘q’, are as defined in the general description) is depictedin Synthetic scheme 1.

The coupling of an amine compound of formula (1) with a carboxylic acidcompound of formula (2) in the presence of a suitable coupling agent(s)and a base gives the compound of formula (Ia). The suitable couplingagent(s) used in the reaction may be1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), propylphosphonicanhydride (T₃P), N,N′-dicyclohexylcarbodiimide (DCC) or(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU). The suitable base used in thereaction may be Et₃N, DIPEA, pyridine or DMAP. The coupling reaction maybe carried out in a suitable solvent or mixture thereof. The suitablesolvent may be selected from CH₂Cl₂, CHCl₃, DMF and THF or a combinationthereof. Alternatively, the coupling of an amine compound of formula (1)with a carboxylic acid compound of formula (3) in the presence of asuitable coupling agent(s) and suitable base gives the amide compound offormula (4). The reduction of the ketone group of the compound offormula (4) using a suitable reducing agent in a suitable solvent givesthe corresponding racemic hydroxyl compound of formula (Ib). Thesuitable reducing agent used in the reaction may be sodium borohydrideand the suitable solvent may be methanol or THF of combination thereof.

A general approach for the preparation of compounds of general formula(II) (wherein ring A, ring B, L, R², R³, R⁴, R⁵, ‘n’, ‘m’, ‘q’ and ‘p’are as defined in the general description and R⁶ is C₁₋₈alkyl) isdepicted in Synthetic scheme 2.

The coupling of an amine compound of formula (1) with a carboxylic acidcompound of formula (5) in the presence of a suitable coupling agent(s)and base gives the compound of formula (II). The suitable coupling agentused in the reaction may be propylphosphonic anhydride (T₃P) or HATU.The suitable base used may be DIPEA, pyridine or DMAP. The couplingreaction may be carried out in a suitable solvent or mixture thereof.The suitable solvent may be selected from CHCl₃, DMF, CH₂Cl₂ and THF orcombination thereof.

A general approach for the preparation of compound of formula (1a)(wherein ring B, R², R³, R⁴ ‘m’, ‘n’ and ‘p’ are as defined in thegeneral description and any one or two of X¹, X², X³ and X⁴ is/are N andthe others are CH) is depicted in Synthetic scheme 3.

The reaction of a suitably substituted dihalo compound of formula (6)(wherein Hal is halogen) with a substituted boronic acid compound offormula (7) using a palladium catalyst in the presence of a suitablebase and in a suitable solvent gives a compound of formula (8). Thesuitable base used in the reaction may be sodium carbonate, potassiumcarbonate or cesium carbonate. The suitable solvent used in the reactionmay be independently selected from THF, DMSO, water and CH₂Cl₂, orcombination thereof. The reaction of a compound of formula (8) with asuitably substituted 4-aminophenylboronic acid, pinacol ester compoundof formula (9) using a palladium catalyst in the presence of a suitablebase gives the substituted aniline compound of formula (Ia). Thesuitable base used in the reaction may be Na₂CO₃, K₂CO₃, DIPEA, pyridineor DMAP. The reaction may be carried out in a suitable solvent ormixture thereof. The suitable solvent may be selected from 1,4-dioxane,DMSO, water, DMF and THF or combination thereof.

Another approach for the preparation of compound of formula (Ia)(wherein ring B, R², R³, R⁴, ‘m’, ‘n’, and ‘p’ are as defined in thegeneral description and any one or two of X¹, X², X³ and X⁴ is/are N andthe others are CH) is depicted in synthetic scheme 4.

The reaction of a suitably substituted di-halo compound of formula (6)(wherein Hal is halogen) with a suitably substituted4-nitrophenylboronic acid, pinacol ester compound of formula (10) usinga palladium catalyst in the presence of a suitable base and in asuitable solvent gives the compound of formula (11). The suitable baseused in the reaction may be sodium carbonate, potassium carbonate orcesium carbonate. The solvent may be selected from DMSO, DMF, water or amixture thereof. The reaction of the nitro compound of formula (11) witha substituted boronic acid compound of formula (7) using a palladiumcatalyst in the presence of a suitable base and in a suitable solventgives the compound of formula (12). The suitable base used in thereaction may be sodium carbonate. The suitable solvent may be selectedfrom DMSO, water, DMF and THF or combination thereof. Alternatively, thereaction of a substituted di-halo compound of formula (6) with asubstituted boronic acid compound of formula (7) using a palladiumcatalyst in the presence of a suitable base and in a suitable solventgives the compound of general formula (8) which on reaction with a4-nitrophenylboronic acid, pinacol ester compound of formula (10) usinga palladium catalyst in the presence of a suitable base and in asuitable solvent furnishes compound of formula (12) under the samereaction conditions as mentioned above. The reduction of the nitro groupof the compound of formula (12) using iron powder in the presence ofaqueous acetic acid or ammonium chloride gives the corresponding aminecompound of formula (1a). The solvent used in the reaction can beselected from ethanol, water, DMF, DMSO or a mixture thereof.

A general approach for the preparation of compound of formula (1b)(wherein R², R³, R⁴, ‘m’, ‘n’ and ‘p’ are as defined in the generaldescription and X⁵ is C, N or O) is depicted in the Synthetic Scheme 5.

The reaction of a suitably substituted di-halo compound of formula (6a)(wherein Hal is halogen) with the hetero alicyclic compound of formula(13) in the presence of a base and in a suitable solvent gives thecompound of formula (14). The suitable base used in the reaction may bepotassium carbonate, sodium carbonate or cesium fluoride. The reactionmay be carried out in a suitable solvent or mixture thereof. Thesuitable solvent may be selected from CH₂Cl₂, CHCl₃, DMF and THF orcombination thereof. The compound of formula (14) on reaction with asuitably substituted 4-aminophenylboronic acid, pinacol ester compoundof formula (9) using a palladium catalyst in the presence of a suitablebase gives the aniline compound of formula (Ib). The suitable base usedin the reaction may be potassium carbonate, sodium carbonate,triethylamine or DIPEA. The reaction may be carried out in a suitablesolvent or mixture thereof. The suitable solvent may be selected fromCH₂Cl₂, CHCl₃, DMF, acetonitrile or THF or combination thereof.

A general approach for the preparation of compound of formula (1c)(wherein R², R³, R⁴, ‘n’ and ‘p’ are as defined in the generaldescription) is depicted in the Synthetic Scheme 6.

The condensation of a suitably substituted acetophenone compound offormula (15) with a hydrazine derivative (16) in a suitable solventgives the pyrazole coupled substituted phenyl compound of formula (17).The reaction may be carried out in a suitable solvent or mixturethereof. The suitable solvent may be selected from ethanol, CH₂Cl₂,CHCl₃, DMF and THF or combination thereof. The selective bromination ofa compound of formula (17) using N-bromosuccinimide (NBS) in a suitablesolvent such as DMF or THF yields a compound of formula (18). Thereaction of a compound of formula (18) with a suitably substituted4-nitrophenylboronic acid, pinacol ester compound of formula (10) in thepresence of a suitable base and solvent followed by the reduction of thenitro group using iron powder in the presence of aqueous acetic acid orammonium chloride gives the corresponding amine compound of formula(1c). The suitable base used in the coupling reaction may be Na₂CO₃,Et₃N, DIPEA, pyridine or DMAP. The suitable solvent may be selected fromethanol, DMSO, water, CH₂Cl₂, DMF and THF or combination thereof.

A general approach for the preparation of compound of formula (1d)(wherein R², R⁴, ‘n’, and ‘p’ are as defined in the general descriptionand R⁷ is C₁₋₈alkyl or haloC₁₋₈alkyl) is depicted in the SyntheticScheme 7.

The reaction of a suitably substituted acetophenone compound of formula(15) with an ethyl ester compound of formula (19) in the presence of abase and in a suitable solvent gives the compound of formula (20). Thesuitable base used in the reaction may be sodium hydride, sodiummethoxide (25% in methanol), DIPEA or pyridine. The suitable solvent maybe selected from methyl tert-butyl ether, CHCl₃, DMF and THF orcombination thereof. The reaction of compound of formula (20) with asuitably substituted phenyl hydrazine compound of formula (21) in asuitable solvent gives the pyrazole coupled substituted phenyl compoundof formula (22). The suitable solvent may be selected from ethanol,2,2,2-trifluoroethanol, DMF and THF or combination thereof. Thereduction of the nitro group of the compound of formula (22) using ironpowder in the presence of aqueous acetic acid or ammonium chloride givesthe corresponding amine compound of formula (1d). The reaction may becarried out in a suitable solvent selected from ethanol, water, CH₂Cl₂,CHCl₃, DMF and THF or combination thereof.

An approach for the preparation of compound of formula (1e) (wherein R²,R³, R⁴, R^(x), R^(y), X, ‘m’, ‘n’, ‘p’ and ‘t’ are defined in thegeneral description) is depicted in synthetic scheme 8.

The reaction of a suitably substituted di-halo compound of formula (6a)(wherein Hal is halogen) with a suitably substituted4-nitrophenylboronic acid, pinacol ester compound of formula (10) usinga palladium catalyst in the presence of a suitable base and in asuitable solvent gives the compound of formula (11a). The suitable baseused in the reaction may be sodium carbonate, potassium carbonate orcesium carbonate. The solvent may be selected from DMSO, DMF, water or amixture thereof. Halide substitution of the compound of formula (1a)with a compound of formula (23) using a suitable base and in a solventyields the compound of formula (24). The suitable base used in thereaction may be sodium carbonate, potassium carbonate, and cesiumcarbonate or cesium fluoride. The suitable solvent may be selected fromDMSO, water, DMF and THF or combination thereof. Alternatively, thesubstitution reaction of a suitably substituted dihalopyrazine compoundof formula (6a) with a compound of formula (23) using a suitable baseand in a solvent yields a compound of formula (25) which on reactionwith an appropriately substituted 4-nitrophenylboronic acid, pinacolester compound of formula (10) using a palladium catalyst in thepresence of a suitable base and in a suitable solvent furnishes thecompound of formula (24) under the same reaction conditions as describedabove. The reduction of the nitro group of the compound of formula (24)using iron powder in the presence of aqueous acetic acid or ammoniumchloride gives the corresponding amine compound of formula (1e). Thesolvent used in the reaction can be selected from ethanol, water, DMF,DMSO or a mixture thereof.

Another approach for the preparation of compound of formula (1e)(wherein R², R³, R⁴, R^(x), R^(y), X, ‘m’, ‘n’, ‘p’ and ‘t’ are asdefined in the general description) is depicted in Synthetic scheme 9.

The substitution reaction of a suitably substituted di-halo compound offormula (6a) (wherein Hal is halogen) with a compound of formula (23)using a suitable base and solvent yields a compound of formula (25). Thesuitable base used in the reaction may be sodium carbonate, potassiumcarbonate, and cesium carbonate or cesium fluoride. The suitable solventmay be selected from DMSO, water, DMF and THF or combination thereof.The reaction of the compound of formula (25) with a suitably substituted4-aminophenylboronic acid, pinacol ester compound of formula (9) using apalladium catalyst in the presence of a base and suitable solvent givesthe aniline compound of formula (1e). The suitable base used in thereaction may be Na₂CO₃, K₂CO₃ or cesium carbonate. The reaction may becarried out in solvent selected from 1,4-dioxane, DMSO, water, DMF andTHF or combination thereof.

An approach for the preparation of compound of formula (1f) (wherein R²,R³, R⁴, R^(x), R^(y), X, ‘m’, ‘n’, ‘p’ and ‘t’ are as defined in thegeneral description and R⁸ is C₁₋₈alkyl) is depicted in Synthetic scheme10.

The substitution reaction of a suitably substituted di-halo compound offormula (6a) (wherein Hal is halogen) with a compound of formula (26)using a suitable base and solvent yields the compound of formula (27).The suitable base used in the reaction may be sodium carbonate,potassium carbonate, and cesium carbonate or cesium fluoride. Thesuitable solvent may be selected from DMSO, water, DMF and THF orcombination thereof. N-Alkylation of the amine derivative of formula(27) with an appropriate alkyl halide (R⁸—X) in the presence of asuitable base such as sodium hydride and solvent such as THF, DMF or1,4-dioxane furnishes the compound of formula (28). The couplingreaction of the compound of formula (28) with a suitably substituted4-aminophenylboronic acid, pinacol ester compound of formula (9) using apalladium catalyst in the presence of a base and suitable solvent givesthe aniline compound of formula (1f). The suitable base used in thereaction may be Na₂CO₃, K₂CO₃ or cesium carbonate. The reaction may becarried out in a solvent selected from 1,4-dioxane, DMSO, water, DMF andTHF or combination thereof.

A general approach for the preparation of compound of formula (2)(wherein R¹, R⁵ and ‘q’ are as defined in the general description) isdepicted in the Synthetic Scheme 11.

The reaction of a suitably substituted phenyl ketone compound of formula(29) (wherein Hal is halogen) with an ethane 1,2-dithiol in the presenceof a suitable Lewis acid in a suitable solvent gives the thioacetalcompound of formula (30). The suitable Lewis acid used in the reactionmay be boron trifluoride diethyletherate and suitable solvent may beselected from CH₂Cl₂, CHCl₃, DMF and THF. The compound of formula (30)on reaction with a HF-pyridine complex in the presence ofN-iodosuccinimide in a suitable solvent gives the difluoro compound offormula (31). The suitable solvent used in the reaction may be pyridine.The substitution of a halogen group in the compound of formula (31) withtert-butyl acetate in the presence of a palladium catalyst and suitablebase in a suitable solvent gives the ester compound of formula (32). Thesuitable base may be lithium dicyclohexylamine and the suitable solventmay be toluene. The compound of formula (32) on deprotection usingtrifluoroacetic acid in a suitable solvent gives the compound of formula(2). The suitable solvent may be selected from CH₂Cl₂, CHCl₃, DMF andTHF.

A general approach for the preparation of compound of formula (3)(wherein R^(b), R⁵ and ‘q’ are as defined in the general description) isdepicted in the Synthetic Scheme 12.

The condensation of a suitably substituted phenyl acetic acid compoundof formula (33) (wherein Hal is halogen) with ethylbromo(difluoro)acetate (34) in the presence of copper powder and in asuitable solvent gives the difluoro ester compound of formula (35). Thesuitable solvent used in this reaction may be DMSO or DMF. Theprotection of the carboxylic acid (35) with tert-butyl bromide in thepresence of silver carbonate as a base and using a suitable solventyields compound of formula (36). The suitable solvent may be CH₂Cl₂, THFor a mixture thereof. Selective hydrolysis of the ethyl ester in thecompound of formula (36) using lithium hydroxide monohydrate in asuitable solvent gives the acid compound of formula (37). The suitablesolvent may be THF, CH₃OH, water or mixture thereof. The reaction ofcompound (37) with oxalyl chloride gives the corresponding acid chloridewhich on reaction with N,O-dimethylhydroxylamine hydrochloride in thepresence of a base and in a suitable solvent gives the Weinreb amidecompound of formula (38). The suitable solvent used may be CH₂Cl₂ orTHF. The Grignard reaction of the compound of formula (38) with asuitable alkyl magnesium halide of formula R^(b)MgX in a suitablesolvent such as THF gives the difluoroketone compound of formula (39).The ester hydrolysis of compound (39) using trifluoroacetic acid in asuitable solvent gives the acid of formula (3). The suitable solvent maybe selected from CH₂Cl₂, CHCl₃, DMF and THF or combination thereof.

A general approach for the preparation of compound of formula (5)(wherein R⁵ and ‘q’ are as defined in the general description and R⁶ isC₁₋₈alkyl) is depicted in the Synthetic Scheme 13.

The reaction of a suitably substituted di-halo compound of formula (40)(wherein Hal¹ and Hal² are halogen) with ethyl bromo(difluoro)acetate offormula (34) in the presence of copper powder and in a suitable solventgives the difluoro ester compound of formula (41). The suitable solventused in this reaction may be DMSO or DMF. The compound of formula (41)on reduction using a suitable reducing agent and in a suitable solventgives the hydroxyl compound of formula (42). The suitable solvent usedmay be ethanol or methanol and the suitable reducing agent may be sodiumborohydride. The reaction of the compound of formula (42) with analkylating compound of formula (R⁶—X) (where X is halogen) using asuitable base in a suitable solvent gives the compound of formula (43).The suitable base may be sodium hydride and the solvent may be selectedfrom CH₂Cl₂, CHCl₃, DMF and THF or combination thereof. Halidesubstitution of the compound of formula (43) with tert-butyl acetate inthe presence of palladium catalyst in the presence of base and in asuitable solvent gives the compound of formula (44). The suitable baseused in the reaction may be Et₃N, DIPEA, pyridine or DMAP. Thedeprotection of compound (44) using trifluoroacetic acid gives thecarboxylic acid of formula (5). The reaction may be carried out in asuitable solvent or a mixture thereof. The suitable solvent may beselected from CH₂Cl₂, CHCl₃, DMF and THF or combination thereof.

A general approach for the preparation of compounds of the formulae(Ib-i) (wherein ring A, ring B, L, R^(b), R², R³, R⁴, R⁵, ‘n’, ‘m’, ‘p’and ‘q’, are as defined in the general description) is depicted inSynthetic scheme 14.

The reduction of the ketone group of the compound of formula (4) using asuitable chiral reducing agent in a suitable solvent gives one of theisomers of the hydroxyl compound of formula (Ib-i) as a major product.The suitable chiral reducing agent may be selected from (R orS)-2-methyl-CBS-oxazaborolidine in the presence of borane dimethylsulfide, hydrogenation using BINAP-Ru dihalide, H₂/ruthenium(diphosphane)₂ (diamine)₂ complex, etc. The suitable solvent may be THF,DCM or DMF. The obtained isomer may be further purified according tovarious purification techniques known in the art.

Experimental Section

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulfate, filtration and evaporation of the solvent. Purification,unless otherwise mentioned, includes purification by silica gelchromatographic techniques, generally using ethyl acetate/petroleumether mixture of a suitable polarity as the mobile phase. Use of adifferent eluent system is indicated within parentheses.

The abbreviations, symbols and terms used in the examples and assayshave the following meanings throughout: DCM: dichloromethane; DMSO-d₆:Hexadeuterodimethyl sulfoxide; DMSO dimethyl sulfoxide; ¹H NMR: ProtonNuclear Magnetic Resonance; DMF: N,N-dimethyl formamide; EDCI.HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT:1-hydroxybenzotriazole; NaOH: Sodium Hydroxide; KOH: PotassiumHydroxide; LiOH: Lithium Hydroxide; DIPEA: N,N-diisopropylethylamine;THF: Tetrahydofuran; HCl: hydrochloric acid; Na₂SO₄: Sodium sulfate;NaHCO₃: Sodium bicarbonate; J: Coupling constant in units of Hz; h:hour(s); mins: minutes; RT or rt: Room temperature (22-26° C.); o:ortho; m: meta; p: para; APCI-MS: Atmospheric Pressure ChemicalIonization Mass Spectrometry; MHz: Megahertz; aq.: aqueous

INTERMEDIATES Intermediate 1 4-[3-(4-Chlorophenyl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4-chlorophenyl)pyrazine

To a stirred solution of 2,3-dichloropyrazine (500 mg, 3.35 mmol),4-chlorophenyl boronic acid (472 mg, 3.02 mmol) and sodium carbonatemonohydrate (1.2 g, 10.05 mmol) in a mixture of DMSO and water (10 mL,3:1) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (122 mg, 0.16 mmol) at RT. The reaction mixture was degassed andbubbled with nitrogen thrice before heating at 80° C. for 16 h. Themixture was cooled to RT and diluted with ethyl acetate (30 mL). Theorganic solution was washed with water (30 mL) and brine (30 mL). Thesolvent was removed under reduced pressure and the residue obtained waspurified by silica gel column chromatography to obtain 320 mg of thedesired product; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (d, J=7.2 Hz, 2H), 7.76(d, J=7.2 Hz, 2H), 8.35 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H).

Step 2: 4-[3-(4-Chlorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of Step 1 intermediate(310 mg, 1.38 mmol) with 4-aminophenylboronic acid pinacol ester (302mg, 1.38 mmol) using sodium carbonate monohydrate (513 mg, 4.14 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (50 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 2:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 270 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 5.42 (s, 2H), 6.46 (d, J=8.4 Hz,2H), 7.09 (d, J=8.4 Hz, 2H), 7.38-7.47 (m, 4H), 8.51 (s, 1H), 8.57 (s,1H); APCI-MS (m/z) 282 (M+H)⁺.

Intermediate 2 [4-(1,1-Difluoropropyl)phenyl]acetic acid

Step 1: 2-(4-Bromophenyl)-2-ethyl-1,3-dithiolane

To a stirred solution of 4-bromopropiophenone (2.01 g, 9.43 mmol) inanhydrous dichloromethane (20 mL) were added boron trifluoride diethyletherate (0.49 mL, 4.71 mmol) and ethane 1,2-dithiol (1.57 mL, 18.8mmol). The reaction mixture was stirred overnight at RT. The mixture wasdiluted with dichloromethane (10 mL), washed with 10% sodium hydroxidesolution (10 mL), water (20 mL) and brine (20 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to give 2.21 g of the titled product; ¹H NMR (300 MHz, CDCl₃) δ0.89 (t, J=7.5 Hz, 3H), 2.33 (q, J=7.5 Hz, 2H), 3.19-3.32 (m, 2H),3.34-3.41 (m, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H);APCI-MS (m/z) 288 (M)⁺.

Step 2: 1-Bromo-4-(1,1-difluoropropyl)benzene

To a stirred solution of N-iodosuccinimide (704 mg, 3.13 mmol) indichloromethane (5.0 mL) at −20° C. was added hydrogen fluoride inpyridine (70% w/w, 520 μL, 20.88 mmol) and the solution was stirred atthe same temperature for 2 min. A solution of Step 1 intermediate (302mg, 1.04 mmol) in dichloromethane (5.0 mL) was added to the reactionmixture. The resulting mixture was stirred at −20° C. for 30 min. Themixture was diluted with n-hexane (5.0 mL), filtered through basicalumina and washed with n-hexane (30 mL). Filtrate was concentrated andthe residue was diluted with ethyl acetate (50 mL). The combinedfiltrates were washed with 10% sodium thiosulfate (20 mL), 2% potassiumpermanganate (20 mL), water (20 mL) and brine (20 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated. The residuewas purified by silica gel column chromatography to obtain 203 mg of thetitled product; ¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.5 Hz, 3H),2.02-2.21 (m, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H);APCI-MS (m/z) 231 (M−H)−.

Step 3: tert-Butyl [4-(1,1-difluoropropyl)phenyl]acetate

To a stirred solution of dicyclohexylamine (2.04 mL, 10.25 mmol) inanhydrous toluene (20 mL) at 0° C. was added n-butyl lithium (1.6 M,6.41 mL, 10.26 mmol). After 5 min, tert-butyl acetate (1.15 mL, 8.55mmol) was added to the mixture and stirred for 15 min at 0° C. In aseparate flask, tri-tert-butylphosphonium tetrafluoroborate (248 mg,0.85 mmol) and bis(dibenzylideneacetone) palladium (0) (245 mg, 0.42mmol) were mixed and the flask was evacuated and refilled with nitrogenthrice. The solid mixture was taken in toluene (10 mL) and to theresulting suspension was added Step 2 intermediate (2.01 g, 8.55 mmol)followed by the first mixture. The resulting reaction mixture wasstirred overnight at RT. The mixture was diluted with diethyl ether (50mL), filtered through celite bed and washed with diethyl ether (30 mL).The filtrate was concentrated and the residue obtained was purified bysilica gel column chromatography to obtain 1.43 g of the desiredproduct; ¹H NMR (300 MHz, CDCl₃) δ 0.98 (t, J=7.5 Hz, 3H), 1.44 (s, 9H),2.04-2.22 (m, 2H), 3.55 (s, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1Hz, 2H).

Step 4: [4-(1,1-Difluoropropyl)phenyl]acetic acid

To a stirred solution of step 3 intermediate (1.42 g, 5.25 mmol) indichloromethane (20 mL) at 0° C. was added trifluoroacetic acid (10 mL)and the mixture was stirred for 1 h at RT. The solvent in the reactionmixture was evaporated and the residue obtained was purified by silicagel column chromatography to yield 491 mg of the desired product; ¹H NMR(300 MHz, DMSO-d₆) δ 0.90 (t, J=6.0 Hz, 3H), 2.11-2.28 (m, 2H), 3.63 (s,2H), 7.33 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 12.42 (br s, 1H);APCI-MS (m/z) 213 (M−H)−.

Intermediate 3 4-(1,1-Difluoro-2-oxopropyl)phenyl]acetic acid

Step 1: [4-(2-Ethoxy-1,1-difluoro-2-oxoethyl)phenyl]acetic acid

To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol)and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) in a sealed tubewas added ethyl bromodifluoroacetate (196 mg, 1.52 mmol). The reactionmixture was stirred overnight at 60° C. The mixture was cooled to RT,quenched with aqueous ammonium chloride (30 mL), and extracted withethyl acetate (50 mL×2). The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography toobtain 171 mg of the titled product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.22(t, J=6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 12.45 (s, 1H).

Step 2. Ethyl2-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2,2-difluoroacetate

To a stirred solution of Step 1 intermediate (3.3 g, 12.77 mmol) in amixture of dichloromethane and THF (2:1, 90 mL) were added molecularsieves (4 Å, 3.3 g) and silver carbonate (10.6 g, 38.33 mmol). Thereaction mixture was stirred for 15 min, cooled to 0° C. tert-Butylbromide (7.3 mL, 63.89 mmol) was added drop wise to the reactionmixture. The mixture was allowed to attain room temperature and wasstirred overnight. The mixture was filtered through celite bed andwashed with dichloromethane (100 mL). The filtrate was concentratedunder reduced pressure and the residue obtained was purified by columnchromatography to yield 1.82 g of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 1.19 (t, J=6.9 Hz, 3H), 1.37 (s, 9H), 3.64 (s, 2H), 4.28 (q, J=7.2 Hz,2H), 7.41 (d, J=8.4 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H).

Step 3: 2-(4-(2-(tert-Butoxy)-2-oxoethyl)phenyl)-2,2-difluoroacetic acid

To a stirred solution of step 2 intermediate (915 mg, 2.91 mmol) in amixture of THF, methanol and water (3:2:1, 30 mL) at 0° C. was addedlithium hydroxide monohydrate (366 mg, 8.73 mmol) and the mixture wasstirred for 1 h at RT. The reaction mixture was acidified with 1 N HCltill pH 2-3 and extracted with ethyl acetate (50 mL×2). The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford 839 mg of the desired product; ¹H NMR(300 MHz, DMSO-d₆) δ 1.40 (s, 9H), 3.64 (s, 2H), 7.40 (d, J=8.4 Hz, 2H),7.52 (d, J=8.1 Hz, 2H).

Step 4: tert-Butyl(4-{1,1-difluoro-2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)acetate

To a stirred solution of step 3 intermediate (833 mg, 2.90 mmol) indichloromethane (15 mL) at 0° C. were added oxalyl chloride (2.2 mL,4.36 mmol) and catalytic amount of DMF. The reaction mixture was allowedto gradually attain RT and was stirred for 3 h. The reaction mixture wasconcentrated under inert atmosphere to give a residue, which was dilutedwith dichloromethane (15 mL) and cooled to 0° C. Thereafter,N,O-dimethyl hydroxylamine hydrochloride (425 mg, 4.36 mmol) was addedfollowed by triethyl amine (1.6 mL, 11.63 mmol) and the mixture wasstirred overnight at RT. The mixture was diluted with dichloromethane(15 mL), washed with aq. saturated NaHCO₃ solution (20 mL) and brine (20mL). The organic layer was concentrated and the crude obtained waspurified by silica gel column chromatography to yield 581 mg of thetitled product; ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s, 9H), 3.21 (s, 2H),3.56 (s, 5H), 7.34 (d, J=7.8 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H).

Step 5: tert-Butyl [4-(1,1-difluoro-2-oxopropyl)phenyl]acetate

To a stirred solution of step 4 intermediate (572 mg, 1.73 mmol) in THF(15 mL) at 0° C. was added methylmagnesium bromide (1.15 mL, 3.47 mmol)and the mixture was stirred for 2 h. The reaction mixture was quenchedwith aqueous ammonium chloride solution (20 mL) and extracted with ethylacetate (50 mL×2). The combined organic layers were washed with brine(50 mL) and concentrated under reduced pressure. The crude obtained waspurified by silica gel column chromatography to yield 369 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s, 9H), 2.31 (s, 3H), 3.56 (s,2H), 7.36 (d, J=8.4 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H), APCI-MS (m/z) 285(M+H)⁺.

Step 6: 4-(1,1-Difluoro-2-oxopropyl)phenyl]acetic acid

The titled compound was prepared by the reaction of step 5 intermediate(501 mg, 1.76 mmol) with trifluoroacetic acid (10 mL) in dichloromethane(10 mL) as per the procedure described in Step 4 of Intermediate 2 toafford 379 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (s, 3H),3.66 (s, 2H), 7.43 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 12.22 (brs, 1H).

Intermediate 4 4-[3-(3-Chlorophenyl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(3-chlorophenyl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(500 mg, 3.35 mmol) with 3-chlorophenylboronic acid (472 mg, 3.02 mmol)using sodium carbonate monohydrate (1.2 g, 10.05 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (122 mg,0.16 mmol) in a mixture of DMSO and water (15 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 350 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.50 (m, 2H), 7.71 (d, J=7.4 Hz,1H), 7.81 (s, 1H), 8.38 (d, J=1.5 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H).

Step 2: 4-[3-(3-Chlorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(250 mg, 1.11 mmol) with 4-aminophenylboronic acid pinacol ester (243mg, 1.11 mmol) using sodium carbonate monohydrate (412 mg, 3.33 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (36 mg,0.05 mmol) in a mixture of DMSO (15 mL) and water (5.0 mL) at RT as perthe procedure described in Step 1 of Intermediate 1 to yield 273 mg ofthe product. The product was used further without characterization.

Intermediate 5 4-[3-(4-Fluorophenyl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4-fluorophenyl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(3.0 g, 20.13 mmol) with 4-fluorophenylboronic acid (2.68 g, 19.13 mmol)using 2M sodium carbonate solution (30 mL, 60.40 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.16 g,1.00 mmol) in 1,4-dioxane (60 mL) at 90° C. as per the proceduredescribed in Step 1 of Intermediate 1 to yield 1.74 g of the product; ¹HNMR (300 MHz, DMSO-d₆) δ 7.37 (t, J=9.3 Hz, 2H), 7.83 (t, J=8.1 Hz, 2H),8.54 (s, 1H), 8.76 (s, 1H); APCI-MS (m/z) 209 (M+H)⁺.

Step 2: 4-[3-(4-Fluorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(503 mg, 2.39 mmol) with 4-aminophenylboronic acid pinacol ester (787mg, 3.59 mmol) in the presence of bis(dibenzylidene)acetone palladium(0) (276 mg, 0.23 mmol) using 2M sodium carbonate solution (2.9 mL, 5.99mmol) in a mixture of 1,4-dioxane and water (15 mL, 2:1) at 80° C. asper the procedure described in Step 1 of Intermediate 1 to yield 321 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.38 (s, 2H), 6.44 (d, J=9.0Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 7.44 (t, J=8.1Hz, 2H), 7.46-7.61 (m, 2H).

Intermediate 6 4-[3-(3,4-Difluorophenyl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(3,4-difluorophenyl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(500 mg, 3.35 mmol) with 3,4-difluorophenylboronic acid (477 mg, 3.02mmol) using sodium carbonate monohydrate (1.2 g, 10.05 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (122 mg,0.16 mmol) in a mixture of DMSO and water (15 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 347 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.23-7.34 (m, 1H), 7.59-7.72 (m, 2H),8.37 (d, J=1.8 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H).

Step 2: 4-[3-(3,4-Difluorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(250 mg, 1.10 mmol) with 4-aminophenylboronic acid pinacol ester (290mg, 1.10 mmol) using sodium carbonate monohydrate (409 mg, 3.33 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (40 mg,0.05 mmol) in a mixture of DMSO and water (15 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 256 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 5.44 (s, 2H), 6.48 (d, J=8.4 Hz,2H), 7.09 (d, J=8.4 Hz, 2H), 7.20-7.26 (m, 1H), 7.40-7.50 (m, 2H), 8.54(s, 1H), 8.60 (s, 1H).

Intermediate 7 4-[3-(4,4-Difluoropiperidin-1-yl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4,4-difluoropiperidin-1-yl)pyrazine

To the stirred solution of 2,3-dichloropyrazine (973 mg, 6.53 mmol) inDMF (10 mL) was added 4,4-difluoropiperidine hydrochloride (1.03 g, 6.53mmol) and potassium carbonate (2.7 g, 19.59 mmol) and the resultantmixture was stirred for 16 h at 60° C. The reaction mixture was cooledto RT, diluted with water (50 mL) and extracted with ethyl acetate (100mL). The organic layer was washed with brine (30 mL) and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography to obtain 1.12 g of the titled product; 1H NMR(300 MHz, CDCl₃) δ 2.08-2.21 (m, 4H), 3.58 (q, J=6.6 Hz, 4H), 7.92 (d,J=2.4 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H).

Step 2: 4-[3-(4,4-Difluoropiperidin-1-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(500 mg, 2.14 mmol) with 4-aminophenylboronic acid pinacol ester (703mg, 3.21 mmol) using sodium carbonate monohydrate (796 mg, 6.42 mmol) inthe presence of tetrakis(triphenylphosphine)palladium(0) (247 mg, 0.21mmol) in a mixture of 1,4-dioxane and water (10 mL, 2:1) at 80° C. asper the procedure described in Step 1 of Intermediate 1 to yield 316 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.90-2.12 (m, 4H), 3.18-3.26(m, 4H), 5.46 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H),8.02 (d, J=1.8 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H).

Intermediate 8 4-[3-(Morpholin-4-yl)pyrazin-2-yl]aniline

Step 1: 4-(3-Chloropyrazin-2-yl)morpholine

A mixture of 2,3-dichloropyrazine (1.2 g, 8.05 mmol) and morpholine (700mg, 8.05 mmol) in ethanol (10 mL) was refluxed overnight. The mixturewas cooled to RT, diluted with ethyl acetate (30 mL) and washed withwater (30 mL) followed by brine (40 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography toyield 1.57 g of the desired product; ¹H NMR (300 MHz, CDCl₃) δ 3.46 (t,J=6.9 Hz, 4H), 3.86 (t, J=6.9 Hz, 4H), 7.91 (d, J=2.4 Hz, 1H), 8.12 (d,J=2.4 Hz, 1H).

Step 2: 4-[3-(Morpholin-4-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(500 mg, 2.36 mmol) with 4-aminophenylboronic acid pinacol ester (518mg, 2.36 mmol) using sodium carbonate monohydrate (879 mg, 7.09 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (86 mg,0.11 mmol) in a mixture of DMSO and water (15 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 150 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 3.05 (t, J=4.8 Hz, 4H), 3.63 (t,J=4.8 Hz, 4H), 5.45 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz,1H), 8.02 (d, J=2.4 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H).

Intermediate 94-[1-tert-Butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]aniline

Step 1: 1-tert-Butyl-5-(4-fluorophenyl)-1H-pyrazole

A mixture of 4-fluoroacetophenone (2.01 g, 14.47 mmol) andN,N′-dimethylformamide dimethyl acetal (2.07 g, 17.4 mmol) in DMF (20mL) was heated at 80° C. for 1.5 h. The mixture was concentrated underreduced pressure. To the residue were added ethanol (20 mL) andtert-butyl hydrazine hydrochloride (5.41 g, 43.61 mmol). The mixture washeated at 70° C. for 5 h before cooled to RT and poured into water (70mL). The precipitated solid was filtered, washed with water (20 mL) anddried under vacuum to give 841 mg of the desired product; ¹H NMR (300MHz, CDCl₃) δ 1.46 (s, 9H), 6.14 (s, 1H), 7.08 (t, J=8.4, 2H), 7.25-7.34(m, 2H), 7.47 (s, 1H).

Step 2: 4-Bromo-1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole

To a stirred solution of step 1 intermediate (803 mg, 3.67 mmol) inanhydrous DMF (8.0 mL) was added N-bromosuccinimide (720 mg, 4.04 mmol)and the mixture was stirred at RT for 1 h. The reaction mixture waspoured into water (50 mL), the precipitated solid was filtered, washedwith water (10 mL) and dried well to obtain 981 mg of the titledproduct; ¹H NMR (300 MHz, CDCl₃) δ 1.43 (s, 9H), 7.15 (t, J=8.7, 2H),7.25-7.30 (m, 2H), 7.49 (s, 1H)

Step 3: 1-tert-Butyl-5-(4-fluorophenyl)-4-(4-nitrophenyl)-1H-pyrazole

The titled compound was prepared by the reaction of step 2 intermediate(603 mg, 2.02 mmol) with 4-nitrophenylboronic acid pinacol ester (505mg, 2.02 mmol) using sodium carbonate monohydrate (754 mg, 6.08 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (74 mg,0.10 mmol) in a mixture of DMSO and water (3:1, 10 mL) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 321 mg of theproduct; 1H NMR (300 MHz, DMSO-d₆) δ 1.4 (s, 9H), 7.24-7.38 (m, 4H),7.51 (t, J=5.7 Hz, 2H), 7.97-8.09 (m, 3H).

Step 4: 4-[1-tert-Butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]aniline

To a suspension of step 3 intermediate (306 mg, 0.90 mmol) and ammoniumchloride (482 mg, 9.01 mmol) in a mixture of ethanol and water (1:1, 10mL) at 70° C. was added iron powder (151 mg, 2.70 mmol) and theresulting mixture was stirred at 100° C. for 1 h. The reaction mixturewas cooled to RT, poured into saturated aqueous NaHCO₃ solution andextracted with ethyl acetate (50 mL×2). The organic layer was dried welland concentrated. The residue obtained was purified by silica gel columnchromatography to yield 210 mg of the titled compound; ¹H NMR (300 MHz,DMSO-d₆) δ 1.35 (s, 9H), 4.89 (s, 2H), 6.31 (d, J=8.1 Hz, 2H), 6.66 (d,J=7.8 Hz, 2H), 7.24 (t, J=8.7 Hz, 2H), 7.38 (t, J=8.1 Hz, 2H), 7.54 (s,1H).

Intermediate 10 [4-(1,1-Difluoro-2-methoxyethyl)phenyl]acetic acid

Step 1: Ethyl (4-bromophenyl)(difluoro)acetate

The titled compound was prepared by the reaction of1-bromo-4-iodobenzene (1.0 g, 3.55 mmol) with ethyl bromodifluoroacetate(1.43 g, 7.06 mmol) using copper powder (903 mg, 14.2 mmol) in DMSO (10mL) as per the procedure described in Step 1 of Intermediate 3 to give623 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 1.30 (t, J=7.2 Hz, 3H),4.29 (q, J=7.2 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H).

Step 2: 2-(4-Bromophenyl)-2,2-difluoroethanol

To a stirred solution of Step 1 intermediate (206 mg, 0.73 mmol) inethanol (4.0 mL) at −10° C. was added calcium chloride (25 mg, 0.22mmol) followed by sodium borohydride (70 mg, 1.84 mmol). The resultingmixture was stirred at RT for 2 h. The reaction mixture was quenchedwith aq. saturated NaHCO₃ solution (10 mL) and extracted with ethylacetate (40 mL×2). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography to obtain 176 mg of the titled product; ¹H NMR (300 MHz,CDCl₃) δ 3.95 (t, J=13.2 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.1Hz, 2H).

Step 3: 1-Bromo-4-(1,1-difluoro-2-methoxyethyl)benzene

To a stirred solution of Step 2 intermediate (170 mg, 0.71 mmol) inanhydrous DMF (20 mL) was added sodium hydride (60% w/w, 37 mg, 0.93mmol) at 0° C. After 15 min was added methyl iodide (68 μL, 1.07 mmol)and the mixture was stirred at RT for 2 h. The reaction mixture wasquenched with water (30 mL) and extracted with ethyl acetate (2×50 mL).The combined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography toyield 141 mg of the titled product; ¹H NMR (300 MHz, CDCl₃) δ 3.42 (s,3H), 3.78 (t, J=12.6 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.4 Hz,2H).

Step 4: tert-Butyl [4-(1,1-difluoro-2-methoxyethyl)phenyl]acetate

The titled compound was prepared by the reaction of Step 3 intermediate(506 mg, 2.01 mmol) with tert-butyl acetate (272 μL, 2.01 mmol) in thepresence of n-butyl lithium (1.51 mL, 2.41 mmol),tri-tert-butylphosphonium tetrafluoroborate (58 mg, 0.20 mmol),bis(dibenzylidene)acetone palladium (0) (58 mg, 0.10 mmol) anddicyclohexylamine (782 μL, 2.41 mmol) in toluene (10 mL) as per theprocedure described in Step 3 of Intermediate 2 to yield 398 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 1.44 (s, 9H), 3.43 (s, 3H), 3.55 (s,3H), 3.79 (t, J=13.2 Hz, 2H), 7.36 (d, J=13.8 Hz, 2H), 7.46 (d, J=8.4Hz, 2H); ESI-MS (m/z) 283 (M−H)−.

Step 5: [4-(1,1-Difluoro-2-methoxyethyl)phenyl]acetic acid

The titled compound was prepared by the reaction of Step 4 intermediate(386 mg, 1.38 mmol) with trifluoroacetic acid (3.0 mL) indichloromethane (6.0 mL) as per the procedure described in Step 4 ofIntermediate 2 to afford 161 mg of the product; ¹H NMR (300 MHz,DMSO-d₆) δ 3.31 (s, 3H), 3.62 (s, 2H), 3.86 (t, J=14.1 Hz, 2H), 7.35 (d,J=7.8 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 12.41 (br s, 1H).

Intermediate 11 4-[3-(2-Chlorophenyl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(1.44 g, 9.62 mmol) with 4-nitrophenylboronic acid pinacol ester (2.01g, 8.05 mmol) using sodium carbonate (2.99 g, 24.19 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (294 mg,0.40 mmol) in a mixture of DMSO and water (20 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 1.12 g of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=9.0 Hz, 2H), 8.35 (d,J=8.7 Hz, 2H), 8.44 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H).

Step 2: 2-(2-Chlorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of Step 1 intermediate(305 mg, 3.35 mmol) with 2-chlorophenylboronic acid (246 mg, 1.57 mmol)using sodium carbonate monohydrate (417 mg, 3.93 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (48 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 149 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.42 (m, 4H), 7.59 (d, J=8.7 Hz,2H), 8.12 (d, J=9.3 Hz, 2H), 8.74 (d, J=5.4 Hz, 2H).

Step 3: 4-[3-(2-Chlorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(140 mg, 0.44 mmol) using iron powder (75 mg, 1.34 mmol) and ammoniumchloride (240 mg, 4.49 mmol) in a mixture of ethanol and water (10 mL,1:1) as per the procedure described in Step 4 of Intermediate 9 to yield110 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.36 (s, 2H), 6.36(d, J=7.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.42 (br s, 4H), 8.53 (s,1H), 8.65 (s, 1H).

Intermediate 12 4-[3-(4-Chloro-2-fluorophenyl)pyrazin-2-yl]aniline

Step 1: 2-(4-Chloro-2-fluorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (403 mg,1.73 mmol) with 4-chloro-2-fluorophenylboronic acid (362 mg, 2.07 mmol)using sodium carbonate monohydrate (550 mg, 5.19 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63.3 mg,0.08 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 376 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 6.99 (d, J=9.6 Hz, 1H), 7.29 (t,J=8.1 Hz, 1H), 7.55-7.65 (m, 3H), 8.18 (d, J=8.7 Hz, 2H), 8.73 (s, 2H).

Step 2: 4-[3-(4-Chloro-2-fluorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(367 mg, 1.11 mmol) using iron powder (186 mg, 3.33 mmol) and ammoniumchloride (595 mg, 11.13 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield240 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.42 (s, 2H), 6.44(d, J=8.1 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.59(t, J=7.2 Hz, 1H), 8.57 (s, 1H), 8.66 (s, 1H).

Intermediate 13 4-[3-(2,4-Difluorophenyl)pyrazin-2-yl]aniline

Step 1: 2-(2,4-Difluorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (503 mg,2.16 mmol) with 2,4-difluorophenylboronic acid (409 mg, 2.59 mmol) usingsodium carbonate monohydrate (687 mg, 6.48 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (79 mg,0.10 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 365 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 6.66-6.75 (m, 1H), 7.04 (t, J=6.3 Hz,1H), 7.60-7.68 (m, 3H), 8.17 (d, J=9.0 Hz, 2H), 8.72 (s, 2H).

Step 2: 4-[3-(2,4-Difluorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(351 mg, 1.12 mmol) using iron powder (187 mg, 3.36 mmol) and ammoniumchloride (600 mg, 11.20 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield203 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.36 (s, 2H), 6.42(d, J=8.1 Hz, 2H), 7.06 (d, J=8.1 Hz, 2H), 7.18 (t, J=8.7 Hz, 3H), 7.58(q, J=6.9 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H).

Intermediate 14 4-[3-(4-Chlorophenyl)pyridin-2-yl]aniline

Step 1: 3-Bromo-2-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of 2,3-dibromopyridine(1.0 g, 4.22 mmol) with 4-nitrophenylboronic acid pinacol ester (1.26 g,5.06 mmol) using potassium carbonate (1.75 g, 12.66 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (172 mg,0.21 mmol) in a mixture of DMSO and water (25 mL, 4:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 658 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.21-7.28 (m, 1H), 7.88 (d, J=9.0 Hz,2H), 8.06 (d, J=7.8 Hz, 1H), 8.34 (d, J=8.7 Hz, 2H), 8.68 (d, J=4.5 Hz,1H).

Step 2: 3-(4-Chlorophenyl)-2-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of Step 1 intermediate(250 mg, 0.89 mmol) with 4-chlorophenylboronic acid (209 mg, 1.34 mmol)using potassium carbonate (371 mg, 2.69 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (73 mg,0.08 mmol) in a mixture of DMSO and water (12 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 227 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 7.23 (d, J=8.1 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H), 7.57 (t, J=8.4 Hz, 3H), 7.92 (d, J=8.4 Hz, 1H), 8.16 (d,J=8.4 Hz, 2H), 8.74 (d, J=4.8 Hz, 1H).

Step 3: 4-[3-(4-Chlorophenyl)pyridin-2-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(220 mg, 0.70 mmol) using iron powder (198 mg, 3.54 mmol) and ammoniumchloride (379 mg, 7.08 mmol) in a mixture of ethanol (15 mL) and water(3.0 mL) as per the procedure described in Step 4 of Intermediate 9 toyield 178 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.25 (br s,2H), 6.41 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.4 Hz,2H), 7.30-7.41 (m, 3H), 7.70 (d, J=6.3 Hz, 1H), 8.58 (d, J=4.5 Hz, 1H).

Intermediate 15 4-[3-(2-Fluorophenyl)pyrazin-2-yl]aniline

Step 1: 2-(2-Fluorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (306 mg,1.31 mmol) with 2-fluorophenylboronic acid (221 mg, 1.57 mmol) usingsodium carbonate monohydrate (419 mg, 3.95 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (48 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 348 mg of theproduct; 1H NMR (300 MHz, CDCl₃) δ 6.94 (t, J=9.0 Hz, 1H), 7.29 (t,J=9.3 Hz, 1H), 7.38-7.45 (m, 1H), 7.62 (d, J=8.7 Hz, 3H), 8.15 (d, J=9.0Hz, 2H), 8.72 (d, J=2.1 Hz, 2H).

Step 2: 4-[3-(2-Fluorophenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(312 mg, 1.05 mmol) using iron powder (177 mg, 3.16 mmol) and ammoniumchloride (565 mg, 10.56 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield211 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.38 (s, 2H), 6.40(d, J=8.4 Hz, 2H), 7.04-7.17 (m, 3H), 7.29 (t, J=7.2 Hz, 1H), 7.42-7.57(m, 2H), 8.55 (s, 1H), 8.64 (d, J=2.1 Hz, 1H); APCI-MS (m/z) 266 (M+H)⁺.

Intermediate 16 4-{3-[4-(Trifluoromethyl)phenyl]pyrazin-2-yl}aniline

Step 1: 2-(4-Nitrophenyl)-3-[4-(trifluoromethyl)phenyl]pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (308 mg,1.32 mmol) with 4-trifluoromethyl phenylboronic acid (301 mg, 1.58 mmol)using sodium carbonate monohydrate (421 mg, 3.97 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (48 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 371 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.67 (m, 6H), 8.19 (d, J=9.0 Hz,2H), 8.71 (s, 2H).

Step 2: 4-{3-[4-(Trifluoromethyl)phenyl]pyrazin-2-yl}aniline

The titled compound was prepared by the reduction of Step 1 intermediate(346 mg, 1.00 mmol) using iron powder (167 mg, 3.00 mmol) and ammoniumchloride (536 mg, 10.02 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield241 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.42 (s, 2H), 6.44(d, J=8.4 Hz, 2H), 7.05 (d, J=7.8 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.71(d, J=8.4 Hz, 2H), 8.56 (s, 1H), 8.61 (s, 1H); APCI-MS (m/z) 316 (M+H)⁺.

Intermediate 17 4-[3-(4-Methylphenyl)pyrazin-2-yl]aniline

Step 1: 2-(4-Methylphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (300 mg,1.28 mmol) with 4-methyl phenylboronic acid (210 mg, 1.54 mmol) usingsodium carbonate monohydrate (410 mg, 3.86 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (47.14 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 248 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H), 7.15 (d, J=7.8 Hz, 2H),7.30 (t, J=7.8 Hz, 2H), 8.18 (d, J=8.7 Hz, 2H), 8.65 (d, J=11.4 Hz, 2H).

Step 2: 4-[3-(4-Methylphenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(240 mg, 0.83 mmol) using iron powder (139 mg, 2.49 mmol) and ammoniumchloride (445 mg, 8.32 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield176 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 5.37(s, 2H), 6.44 (d, J=7.8 Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 8.51 (d, J=9.0 Hz, 2H).

Intermediate 18 4-[3-(4-Fluorophenyl)pyridin-2-yl]aniline

Step 1: 3-(4-Fluorophenyl)-2-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of3-bromo-2-(4-nitrophenyl)pyridine (Step 1 of Intermediate 14) (250 mg,0.89 mmol) with 4-fluorophenyl boronic acid (188 mg, 1.34 mmol) usingpotassium carbonate (371 mg, 2.69 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (73 mg,0.08 mmol) in a mixture of DMSO and water (12 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 238 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.02 (t, J=8.7 Hz, 2H), 7.10-7.17 (m,2H), 7.41-7.46 (m, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.77 (d, J=7.8 Hz, 1H),8.12 (d, J=8.4 Hz, 2H), 8.74 (d, J=4.5 Hz, 1H).

Step 2: 4-[3-(4-Fluorophenyl)pyridin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(230 mg, 0.78 mmol) using iron powder (218 mg, 3.91 mmol) and ammoniumchloride (418 mg, 7.81 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield164 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.22 (s, 2H), 6.39(d, J=8.7 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H), 7.13-7.24 (m, 4H), 7.29-7.33(m, 1H), 7.69 (d, J=7.2 Hz, 1H), 8.55 (s, 1H).

Intermediate 19 4-(3-Phenylpyrazin-2-yl)aniline

Step 1: 2-(4-Nitrophenyl)-3-phenylpyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (403 mg,1.73 mmol) with phenylboronic acid (253 mg, 2.07 mmol) using sodiumcarbonate monohydrate (550 mg, 5.19 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63 mg,0.08 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 356 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.45 (m, 5H), 7.64 (d, J=8.7 Hz,2H), 8.16 (d, J=9.0 Hz, 2H), 8.68 (d, J=9.0 Hz, 2H).

Step 2: 4-(3-Phenylpyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(341 mg, 1.22 mmol) using iron powder (206 mg, 3.68 mmol) and ammoniumchloride (657 mg, 12.29 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield219 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.39 (s, 2H), 6.44(d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.33-7.42 (m, 5H), 8.52 (s,1H), 8.57 (s, 1H).

Intermediate 20 4-[3-(4-Aminophenyl)pyrazin-2-yl]benzonitrile

Step 1: 4-(3-Chloropyrazin-2-yl)benzonitrile

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(1.0 g, 6.77 mmol) with 4-cyanophenylboronic acid (896 mg, 6.10 mmol)using sodium carbonate monohydrate (2.5 g, 20.32 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (245 mg,0.33 mmol) in a mixture of DMSO and water (25 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 810 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.1 Hz, 2H), 7.95 (d,J=8.4 Hz, 2H), 8.43 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H).

Step 2: 4-[3-(4-Nitrophenyl)pyrazin-2-yl]benzonitrile

The titled compound was prepared by the reaction of Step 1 intermediate(503 mg, 2.33 mmol) with 4-nitrophenylboronic acid pinacol ester (581mg, 2.33 mmol) using sodium carbonate monohydrate (867 mg, 6.99 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (85 mg,0.11 mmol) in a mixture of DMSO and water (3:1, 10 mL) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 526 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.55-7.66 (m, 6H), 8.20 (d, J=8.1 Hz,2H), 8.73 (s, 2H).

Step 3: 4-[3-(4-Aminophenyl)pyrazin-2-yl]benzonitrile

The titled compound was prepared by the reduction of Step 2 intermediate(503 mg, 1.66 mmol) using iron powder (279 mg, 4.99 mmol) and ammoniumchloride (890 mg, 16.64 mmol) in a mixture of ethanol and water (10 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield313 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.42 (s, 2H), 6.45(d, J=8.1 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.59 (d, J=7.8 Hz, 2H), 7.80(d, J=8.1 Hz, 2H), 8.55 (s, 1H), 8.62 (s, 1H).

Intermediate 21 4-[3-(Pyridin-4-yl)pyrazin-2-yl]aniline

Step 1: 2-(4-Nitrophenyl)-3-(pyridin-4-yl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (300 mg,1.27 mmol) with pyridine 4-boronic acid (188 mg, 1.52 mmol) usingpotassium carbonate (528 mg, 3.82 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (52 mg,0.06 mmol) in a mixture of DMSO and water (16 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 208 mg of theproduct; 1H NMR (300 MHz, DMSO-d₆) δ 7.40 (d, J=4.2 Hz, 2H), 7.69 (d,J=8.1 Hz, 2H), 8.22 (d, J=8.4 Hz, 2H), 8.58 (s, 2H), 8.87 (s, 2H).

Step 2: 4-[3-(Pyridin-4-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(200 mg, 0.71 mmol) using iron powder (200 mg, 3.69 mmol) and ammoniumchloride (384 mg, 7.18 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield132 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.48 (s, 2H), 6.47(d, J=8.1 Hz, 2H), 7.09 (d, J=8.1 Hz, 2H), 7.40 (d, J=5.7 Hz, 2H),8.54-8.65 (m, 4H).

Intermediate 22 4-[5-(4-Fluorophenyl)-3-methyl-1H-pyrazol-1-yl]aniline

Step 1: 1-(4-Fluorophenyl)butane-1,3-dione

To a stirred solution of 4-fluoroacetophenone (1.02 g, 7.38 mmol) inanhydrous THF (10 mL) was added sodium hydride (60% w/w, 886 mg, 22.15mmol) portion wise at RT. The mixture was stirred for 30 min, to it wasadded ethyl acetate (3.0 mL, 29.5 mmol) and it was further stirred at40° C. for 3 h. The mixture was cooled to RT, quenched with 1N HCl andextracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with brine (100 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude compound obtained waspurified by silica gel column chromatography to yield 813 mg of thedesired product; ¹H NMR (300 MHz, CDCl₃) δ 2.19 (s, 3H), 6.13 (s, 1H),7.12 (t, J=8.4 Hz, 2H), 7.89 (t, J=5.4 Hz, 2H), 16.16 (br s, 1H).

Step 2: 5-(4-Fluorophenyl)-3-methyl-1-(4-nitrophenyl)-1H-pyrazole

A mixture of Step 1 intermediate (202 mg, 1.12 mmol) and 4-nitrophenylhydrazine (206 mg, 1.34 mmol) in ethanol (10 mL) was refluxed for 3 h.The solvent was distilled off and the residue thus obtained was purifiedby silica gel column chromatography to yield 231 mg of the titledproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 6.54 (s, 1H),7.21-7.33 (m, 4H), 7.46 (d, J=9.0 Hz, 2H), 8.22 (d, J=8.7 Hz, 2H);ESI-MS (m/z) 298 (M+H)⁺.

Step 3: 4-[5-(4-Fluorophenyl)-3-methyl-1H-pyrazol-1-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(221 mg, 0.74 mmol) using iron powder (125 mg, 2.23 mmol) and ammoniumchloride (408 mg, 7.43 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield151 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.20 (s, 3H), 5.27(s, 2H), 6.33 (s, 1H), 6.48 (d, J=9.0 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H),7.10-7.21 (m, 4H); ESI-MS (m/z) 268 (M+H)⁺.

Intermediate 23 4-[3-(1-Methyl-1H-pyrazol-4-yl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(200 mg, 1.34 mmol) with 1-methylpyrazole-4-boronic acid pinacol ester(335 mg, 1.61 mmol) using potassium carbonate (557 mg, 4.02 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (55 mg,0.06 mmol) in a mixture of DMSO and water (16 mL, 3:1) at 90° C. as perthe procedure described in Step 1 of Intermediate 1 to yield 156 mg ofthe product; ¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (s, 3H), 8.13 (s, 1H),8.30 (s, 1H), 8.52 (s, 1H), 8.61 (s, 1H).

Step 2: 4-[3-(1-Methyl-1H-pyrazol-4-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reaction of step 1 intermediate(150 mg, 0.77 mmol) with 4-aminophenylboronic acid pinacol ester (203mg, 0.92 mmol) using 2M sodium carbonate solution (1.2 mL, 2.31 mmol)and tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.07 mmol) in 1,4dioxane (2.3 mL) at 90° C. as per the procedure described in Step 1 ofIntermediate 1 to yield 86 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 3.78 (s, 3H), 5.43 (s, 2H), 6.60 (d, J=8.4 Hz, 2H), 7.17 (t, J=8.1 Hz,3H), 7.74 (s, 1H), 8.41 (d, J=9.3 Hz, 2H).

Intermediate 241-{4-[3-(4-Aminophenyl)pyrazin-2-yl]piperazin-1-yl}ethanone

Step 1: 1-[4-(3-Chloropyrazin-2-yl)piperazin-1-yl]ethanone

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(300 mg, 2.01 mmol) with 1-acetylpiperazine (258 mg, 2.01 mmol) usingpotassium carbonate (278 mg, 2.01 mmol) in acetonitrile (20 mL) at 100°C. as per the procedure described in Step 1 of Intermediate 7 to yield247 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 2.15 (s, 3H), 3.44 (brs, 4H), 3.64 (br s, 2H), 3.77 (br s, 2H), 7.94 (s, 1H), 8.13 (s, 1H).

Step 2: 1-{4-[3-(4-Nitrophenyl)pyrazin-2-yl]piperazin-1-yl}ethanone

The titled compound was prepared by the reaction of Step 1 intermediate(200 mg, 0.83 mmol) with 4-nitrophenylboronic acid pinacol ester (248mg, 0.99 mmol) using potassium carbonate (344 mg, 2.49 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (34 mg,0.04 mmol) in a mixture of DMSO and water (12 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 127 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 2.08 (s, 3H), 3.15-3.26 (m, 4H), 3.48(br s, 2H), 3.61 (br s, 2H), 8.15 (t, J=8.7 Hz, 3H), 8.30 (t, J=8.7 Hz,3H).

Step 3: 1-{4-[3-(4-Aminophenyl)pyrazin-2-yl]piperazin-1-yl}ethanone

The titled compound was prepared by the reduction of Step 2 intermediate(100 mg, 0.30 mmol) using iron powder (85 mg, 1.52 mmol) and ammoniumchloride (163 mg, 3.05 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield87 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.98 (s, 3H), 3.06 (brs, 4H), 3.47 (br s, 4H), 5.46 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 7.70 (d,J=8.4 Hz, 2H), 8.03 (s, 1H), 8.12 (s, 1H); ESI-MS (m/z) 298 (M+H)⁺.

Intermediate 255-[3-(4-Aminophenyl)pyrazin-2-yl]-1-methylpyridin-2(1H)-one

Step 1:1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a stirred suspension of 5-bromo-1-methylpyridin-2(1H)-one (470 mg,2.49 mmol), potassium acetate (736 mg, 7.49 mmol) andbis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethyleneglycol-400 (15 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg,0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80° C.The reaction mixture was cooled to RT, diluted with ethyl acetate (100mL) and washed with water (100 mL) followed by brine (100 mL). Theorganic layer was concentrated and the residue obtained purified byflash column chromatography to afford 160 mg of the titled product; ¹HNMR (300 MHz, CDCl₃) δ 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J=9.3 Hz,1H), 7.60 (d, J=9.0 Hz, 1H), 7.75 (s, 1H); APCI-MS (m/z) 236 (M+H)+.

Step 2: 1-Methyl-5-[3-(4-nitrophenyl)pyrazin-2-yl]pyridin-2(1H)-one

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (90 mg,0.38 mmol) with Step 1 intermediate (100 mg, 0.42 mmol) using potassiumcarbonate (176 mg, 1.27 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (35 mg,0.04 mmol) in a mixture of DMSO and water (12 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 63 mg of theproduct. ¹H NMR (300 MHz, CDCl₃) δ 3.59 (s, 3H), 6.40 (d, J=9.3 Hz, 1H),7.08 (d, J=9.6 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.28 (d,J=8.7 Hz, 2H), 8.61 (s, 2H).

Step 3: 5-[3-(4-Aminophenyl)pyrazin-2-yl]-1-methylpyridin-2(1H)-one

The titled compound was prepared by the reduction of Step 2 intermediate(160 mg, 0.51 mmol) using iron powder (145 mg, 2.59 mmol) and ammoniumchloride (278 mg, 5.19 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield93 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 3.44-3.58 (m, 3H),6.38-6.42 (m, 1H), 7.04 (d, J=7.5 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.26(s, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.50-7.53 (m, 1H), 7.78 (br s, 1H),8.45-8.56 (m, 2H).

Intermediate 26 4-[3-(4-Chlorophenyl)pyrazin-2-yl]-2-fluoroaniline

The titled compound was prepared by the reaction of2-chloro-3-(4-chlorophenyl)pyrazine (Step 1 of Intermediate 1) (300 mg,1.33 mmol) with 4-amino-3-fluorophenylboronic acid pinacol ester (380mg, 1.63 mmol) using potassium carbonate (552 mg, 3.99 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (109 mg,0.13 mmol) in a mixture of DMSO and water (20 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 196 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 3.85-3.89 (m, 2H), 6.82-6.86 (m, 1H),7.03 (d, J=7.2 Hz, 1H), 7.21-7.31 (m, 3H), 7.42 (d, J=8.4 Hz, 2H), 8.56(s, 2H).

Intermediate 27 4-[3-(4-Methoxyphenyl)pyrazin-2-yl]aniline

Step: 2-(4-Methoxyphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (300 mg,1.28 mmol) with 4-methoxyphenylboronic acid (235 mg, 1.54 mmol) usingsodium carbonate monohydrate (410 mg, 3.86 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (47 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 298 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 3.82 (s, 3H), 6.85 (d, J=8.7 Hz, 2H),7.37 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 8.19 (d, J=8.7 Hz, 2H),8.64 (d, J=10.2 Hz, 2H).

Step 2: 4-[3-(4-Methoxyphenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(277 mg, 0.90 mmol) using iron powder (151 mg, 2.70 mmol) and ammoniumchloride (482 mg, 9.13 mmol) in a mixture of ethanol and water (10 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield199 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ δ 3.76 (s, 3H), 5.37(s, 2H), 6.45 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 7.37 (d, J=8.7 Hz, 2H), 8.49 (d, J=10.2 Hz, 2H).

Intermediate 284-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]aniline

Step 1: 4,4,4-Trifluoro-1-(4-fluorophenyl)butane-1,3-dione

The titled compound was prepared by the reaction of 4-fluoroacetophenone(2.1 g, 15.23 mmol) with ethyl trifluoroacetate (2.0 mL, 16.79 mmol)using sodium methoxide (25% in CH₃OH, 1.14 mL, 18.2 mmol) in methylt-butyl ether (4.5 mL) as per the procedure described in Step 1 ofIntermediate 22 to afford 2.10 g of the product; ¹H NMR (300 MHz, CDCl₃)δ 6.53 (s, 1H), 7.10-7.26 (m, 2H), 7.95-8.01 (m, 2H).

Step 2:5-(4-Fluorophenyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole

The titled compound was prepared by the reaction of Step 1 intermediate(1.02 g, 4.35 mmol) with 4-nitrophenylhydrazine (667 mg, 4.35 mmol) in2,2,2-trifluoroethanol (10 mL) as per the procedure described in Step 2of Intermediate 22 to yield 613 mg of the product; 1H NMR (300 MHz,CDCl₃) δ 6.77 (s, 1H), 7.10 (t, J=8.4 Hz, 2H), 7.23 (t, J=4.8 Hz, 2H),7.50 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.4 Hz, 2H).

Step 3:4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(511 mg, 1.59 mmol) using iron powder (266 mg, 4.77 mmol) and ammoniumchloride (850 mg, 15.90 mmol) in a mixture of ethanol and water (10 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield314 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.48 (s, 2H), 6.53(d, J=8.4 Hz, 2H), 6.95 (d, J=8.7 Hz, 2H), 7.10 (s, 1H), 7.21-7.26 (m,2H), 7.30-7.33 (m, 2H).

Intermediate 294-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]aniline

Step 1: 1-(2-Chlorophenyl)-4,4,4-trifluorobutane-1,3-dione

The titled compound was prepared by the reaction of 2-chloroacetophenone(1.10 g, 7.11 mmol) with ethyl trifluoroacetate (929 μL, 7.82 mmol)using sodium methoxide (25% in CH₃OH, 1.84 mL, 8.53 mmol) in methyltert-butyl ether (10 mL) as per the procedure described in Step 1 ofIntermediate 22 to afford 1.05 g of the product; ¹H NMR (300 MHz, CDCl₃)δ 6.57 (s, 1H), 7.32-7.49 (m, 3H), 7.67 (d, J=7.5 Hz, 1H).

Step 2:5-(2-Chlorophenyl)-1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole

The titled compound was prepared by the reaction of Step 1 intermediate(1.12 g, 4.86 mmol) with 4-nitrophenylhydrazine (745 mg, 4.86 mmol) in2,2,2-trifluoroethanol (10 mL) as per the procedure described in Step 2of Intermediate 22 to yield 813 mg of the product; ¹H NMR (300 MHz,CDCl₃) δ 6.80 (s, 1H), 7.25 (s, 2H), 7.35-7.47 (m, 4H), 8.16 (d, J=9.3Hz, 2H).

Step 3:4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(709 mg, 1.93 mmol) using iron powder (323 mg, 5.79 mmol) and ammoniumchloride (1.33 g, 19.32 mmol) in a mixture of ethanol and water (10 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield412 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.38 (s, 2H), 6.44(d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.03 (s, 1H), 7.40-7.51 (m,4H); APCI-MS (m/z) 338 (M+H)⁺

Intermediate 30 4-[3-(2-Chlorophenyl)pyridin-2-yl]aniline

Step 1: 3-(2-Chlorophenyl)-2-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of3-bromo-2-(4-nitrophenyl)pyridine (Step 1 of Intermediate 14) (250 mg,0.89 mmol) with 2-chlorophenylboronic acid (209 mg, 1.34 mmol) usingpotassium carbonate (371 mg, 2.69 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (73 mg,0.08 mmol) in a mixture of DMSO and water (12 mL, 3:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 193 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 7.40-7.62 (m, 7H), 7.86 (d, J=7.8Hz, 1H), 8.11 (d, J=9.0 Hz, 2H), 8.79 (d, J=3.0 Hz, 1H).

Step 2: 4-[3-(2-Chlorophenyl)pyridin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(184 mg, 0.59 mmol) using iron powder (165 mg, 2.96 mmol) and ammoniumchloride (316 mg, 5.92 mmol) in a mixture of ethanol and water (12 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield127 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.17 (s, 2H), 6.31(d, J=8.4 Hz, 2H), 6.94 (d, J=7.8 Hz, 2H), 7.23-7.32 (m, 4H), 7.40-7.43(m, 1H), 7.60 (d, J=7.5 Hz, 1H), 8.58 (s, 1H).

Intermediate 31 4-[3-(2-Methylphenyl)pyrazin-2-yl]aniline

Step 1: 2-(2-Methylphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (309 mg,1.28 mmol) with o-tolylboronic acid (210 mg, 1.54 mmol) using sodiumcarbonate monohydrate (410 mg, 3.86 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (47 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) at 100° C. as perthe procedure described in Step 1 of Intermediate 1 to yield 258 mg ofthe product; ¹H NMR (300 MHz, CDCl₃) δ 2.01 (s, 3H), 7.20-7.33 (s, 4H),7.58 (d, J=8.7 Hz, 2H), 8.10 (d, J=9.0 Hz, 2H), 8.71 (s, 2H); APCI-MS(m/z) 292 (M+H)⁺.

Step 2: 4-[3-(2-Methylphenyl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 1 intermediate(223 mg, 0.76 mmol) using iron powder (128 mg, 2.29 mmol) and ammoniumchloride (410 mg, 7.65 mmol) in a mixture of ethanol and water (10 mL,1:1) as per the procedure described in Step 4 of Intermediate 9 to yield153 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.89 (s, 3H), 5.36(s, 2H), 6.36 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.1 Hz, 2H), 7.20-7.27 (m,4H), 8.52 (s, 1H), 8.61 (s, 1H); APCI-MS (m/z) 262 (M+H)⁺.

Intermediate 32 4-[3-(4-Methylpiperazin-1-yl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4-methylpiperazin-1-yl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(1.0 g, 6.71 mmol) with N-methylpiperazine (988 mg, 9.86 mmol) inacetonitrile (25 mL) at RT as per the procedure described in Step 1 ofIntermediate 7 to yield 658 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ2.40 (s, 3H), 2.58-2.65 (m, 4H), 3.52 (s, 4H), 7.86 (d, J=2.1 Hz, 1H),8.09 (s, 1H).

Step 2: 2-(4-Methylpiperazin-1-yl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of Step 1 intermediate(300 mg, 1.41 mmol) with 4-nitrophenylboronic acid pinacol ester (422mg, 1.69 mmol) using potassium carbonate (585 mg, 4.23 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (58 mg,0.07 mmol) in a mixture of DMSO and water (12 mL, 3:1) at 80° C. as perthe procedure described in Step 1 of Intermediate 1 to yield 208 mg ofthe product; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H), 2.53 (s, 4H), 3.30(s, 4H), 8.12-8.21 (m, 4H), 8.32 (d, J=8.7 Hz, 2H).

Step 3: 4-[3-(4-Methylpiperazin-1-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(200 mg, 0.66 mmol) using iron powder (186 mg, 3.34 mmol) and ammoniumchloride (358 mg, 6.68 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield129 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 2.41 (s, 4H), 2.60 (s,4H), 3.34 (s, 3H), 3.85 (br s, 2H), 6.73 (d, J=8.7 Hz, 2H), 7.74 (d,J=7.8 Hz, 2H), 8.01 (s, 1H), 8.12 (s, 1H); APCI-MS (m/z) 270 (M+H)⁺.

Intermediate 33 4-[3-(4-Ethylpiperazin-1-yl)pyrazin-2-yl]aniline

Step 1: 2-Chloro-3-(4-ethylpiperazin-1-yl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(1.0 g, 6.71 mmol) with N-ethylpiperazine (1.13 g, 9.86 mmol) inacetonitrile (25 mL) as per the procedure described in Step 1 ofIntermediate 7 to yield 958 mg of the product; ESI-MS (m/z) 227 (M+H)⁺.

Step 2: 2-(4-Ethylpiperazin-1-yl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of Step 1 intermediate(300 mg, 1.32 mmol) with 4-nitrophenylboronic acid pinacol ester (396mg, 1.59 mmol) using potassium carbonate (549 mg, 3.97 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (54 mg,0.06 mmol) in a mixture of DMSO and water (12 mL, 3:1) at 80° C. as perthe procedure described in Step 1 of Intermediate 1 to yield 196 mg ofthe product; ¹H NMR (300 MHz, CDCl₃) δ 1.14 (t, J=8.4 Hz, 3H), 2.49-2.56(m, 6H), 3.31 (s, 4H), 8.10-8.22 (m, 4H), 8.30 (d, J=8.4 Hz, 2H);APCI-MS (m/z) 314 (M+H)+.

Step 3: 4-[3-(4-Ethylpiperazin-1-yl)pyrazin-2-yl]aniline

The titled compound was prepared by the reduction of Step 2 intermediate(190 mg, 0.60 mmol) using iron powder (169 mg, 3.03 mmol) and ammoniumchloride (324 mg, 6.06 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield108 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 1.13 (t, J=6.9 Hz, 3H),2.48-2.57 (m, 6H), 3.30 (s, 4H), 3.83 (br s, 2H), 6.72 (d, J=7.8 Hz,2H), 7.73 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 8.09 (s, 1H); APCI-MS (m z)285 (M+H)⁺.

Intermediate 34 4-(2-(4-Chlorophenyl)pyridin-3-yl)aniline

Step 1: 3-Bromo-2-(4-chlorophenyl)pyridine

The titled compound was prepared by the reaction of 2,3-dibromopyridine(803 mg, 3.39 mmol) with 4-chlorophenylboronic acid (530 mg, 3.39 mmol)using sodium carbonate (1.06 g, 10.16 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (124 mg,0.17 mmol) in a mixture of DMSO and water (10 mL, 1:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 378 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.12-7.19 (m, 1H), 7.43 (d, J=8.7 Hz,2H), 7.63 (d, J=8.4 Hz, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.61 (d, J=4.5 Hz,1H); APCI-MS (m/z) 268 (M)⁺, 270 (M+2H)⁺.

Step 2: 4-(2-(4-Chlorophenyl)pyridin-3-yl)aniline

The titled compound was prepared by the reaction of Step 1 intermediate(203 mg, 0.76 mmol) with 4-aminophenylboronic acid pinacol ester (264mg, 0.91 mmol) using sodium carbonate (238 mg, 2.27 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (28 mg,0.04 mmol) in a mixture of DMSO and water (10 mL, 4:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 137 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 5.20 (s, 2H), 6.48 (d, J=8.1 Hz,2H), 7.81 (d, J=8.1 Hz, 2H), 7.32 (s, 4H), 7.38-7.42 (m, 1H), 7.72 (d,J=7.2 Hz, 1H), 8.56 (s, 1H); APCI-MS (m/z) 281 (M+H)⁺,

Intermediate 35 4-(4-(4-Chlorophenyl)pyridin-3-yl)aniline

Step 1: 3-Bromo-4-(4-chlorophenyl)pyridine

The titled compound was prepared by the reaction of 3,4-dibromopyridine(1.02 g, 4.30 mmol) with 4-chlorophenylboronic acid (673 mg, 4.30 mmol)using cesium carbonate (2.10 g, 6.45 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (157 mg,0.22 mmol) in a mixture of DMSO and water (20 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 513 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J=6.9 Hz, 1H), 7.37 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.81 (s,1H); APCI-MS (m/z) 268 (M)⁺, 270 (M+2H)⁺.

Step 2: 4-(4-(4-Chlorophenyl)pyridin-3-yl)aniline

The titled compound was prepared by the reaction of Step 1 intermediate(251 mg, 0.93 mmol) with 4-aminophenylboronic acid pinacol ester (326mg, 1.12 mmol) using sodium carbonate (294 mg, 2.80 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (34 mg,0.05 mmol) in a mixture of DMSO and water (10 mL, 4:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 123 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 5.20 (s, 2H), 6.47 (d, J=8.4 Hz,2H), 6.79 (d, J=7.8 Hz, 2H), 7.20 (t, J=8.4 Hz, 2H), 7.33-7.41 (m, 3H),8.51 (s, 2H).

Intermediate 364-(3-((2S,6R)-2,6-Dimethylmorpholino)pyrazin-2-yl)aniline

Step 1: (2S,6R)-4-(3-Chloropyrazin-2-yl)-2,6-dimethylmorpholine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(200 mg, 1.34 mmol) with (2R,6S)-2,6-dimethylmorpholine (186 mg, 1.61mmol) in the presence of potassium carbonate (278 mg, 2.01 mmol) inacetonitrile (15 mL) as per the procedure described in Step 1 ofIntermediate 7 to yield 252 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ1.24 (d, J=5.7 Hz, 6H), 2.64 (t, J=11.4 Hz, 2H), 3.85 (d, J=12.3 Hz,4H), 7.88 (s, 1H), 8.10 (s, 1H); APCI-MS (m/z) 228 (M+H)⁺.

Step 2: (2S,6R)-2,6-Dimethyl-4-(3-(4-nitrophenyl)pyrazin-2-yl)morpholine

The titled compound was prepared by the reaction of Step 1 intermediate(252 mg, 1.11 mmol) with 4-nitrophenylboronic acid pinacol ester (330mg, 1.33 mmol) using potassium carbonate (459 mg, 3.32 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (45 mg, 0.06 mmol) in a mixture of DMSO andwater (12 mL, 3:1) at 80° C. as per the procedure described in Step 1 ofIntermediate 1 to yield 228 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ1.11 (d, J=5.7 Hz, 6H), 2.55 (t, J=11.1 Hz, 2H), 3.41 (d, J=12.3 Hz,2H), 3.64-3.68 (m, 2H), 8.10-8.22 (m, 4H), 8.32 (d, J=8.4 Hz, 2H).

Step 3: 4-(3-((2S,6R)-2,6-Dimethylmorpholino)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 2 intermediate(215 mg, 0.68 mmol) using iron powder (190 mg, 3.42 mmol) and ammoniumchloride (366 mg, 6.84 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield137 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 1.11 (d, J=6.3 Hz, 6H),2.45 (t, J=12.3 Hz, 2H), 3.48 (d, J=12.3 Hz, 4H), 3.68 (br s, 2H), 6.85(d, J=7.8 Hz, 2H), 7.80 (d, J=7.8 Hz, 2H), 8.03 (s, 1H), 8.11 (s, 1H);APCI-MS (m/z) 285 (M+H)⁺.

Intermediate 374-(5-(2,4-Dichlorophenyl)-3-methyl-1H-pyrazol-1-yl)aniline

Step 1: 1-(2,4-Dichlorophenyl)butane-1,3-dione

The titled compound was prepared by the reaction of2,4-dichloroacetophenone (1.03 g, 5.44 mmol) with ethyl acetate (2.1 mL,21.7 mmol) in the presence of sodium hydride (60% w/w, 653 mg, 16.3mmol) in anhydrous THF (10 mL) as per the procedure described in Step 1of Intermediate 22 to yield 561 mg of the product; ¹H NMR (300 MHz,CDCl₃) δ 2.19 (s, 3H), 6.04 (s, 2H), 7.32 (d, J=6.3 Hz, 1H), 7.45 (s,1H), 7.55 (d, J=8.4 Hz, 1H).

Step 2: 5-(2,4-Dichlorophenyl)-3-methyl-1-(4-nitrophenyl)-1H-pyrazole

The titled compound was prepared by the reaction of Step 1 intermediate(503 mg, 2.17 mmol) with 4-nitrophenyl hydrazine (334 mg, 2.17 mmol) in2,2,2,-trifluoroethanol (5.0 mL) as per the procedure described in Step2 of Intermediate 22 to yield 498 mg of the product; ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 6.55 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.56 (s,2H), 7.74 (s, 1H), 8.22 (d, J=8.7 Hz, 2H); ESI-MS (m/z) 248 (M−H)−.

Step 3: 4-(5-(2,4-Dichlorophenyl)-3-methyl-1H-pyrazol-1-yl)aniline

The titled compound was prepared by the reduction of Step 2 intermediate(496 mg, 1.42 mmol) using iron powder (238 mg, 4.27 mmol) and ammoniumchloride (761 mg, 714.2 mmol) in a mixture of ethanol and water (10 mL,4:1) as per the procedure described in Step 4 of Intermediate 9 to yield210 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 3H), 5.21(s, 2H), 6.30 (s, 1H), 6.43 (d, J=8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H),7.32 (d, J=7.8 Hz, 1H), 7.38-7.43 (m, 1H), 7.67 (d, J=9.9 Hz, 1H);ESI-MS (m/z) 318 (M+H)⁺.

Intermediate 38 4-(3-(2-Chloro-4-fluorophenyl)pyrazin-2-yl)aniline

Step 1: 2-(2-Chloro-4-fluorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (1.0 g,4.24 mmol) with 2-chloro-4-fluorophenylboronic acid (888 mg, 5.09 mmol)using sodium carbonate (1.35 g, 12.73 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (151 mg,0.21 mmol) in a mixture of DMSO and water (20 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 1.14 g of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37 (t, J=8.4 Hz, 1H), 7.48 (d,J=9.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.64-7.69 (m, 1H), 8.20 (d, J=8.7Hz, 2H), 8.86 (d, J=11.4 Hz, 2H); APCI-MS (m/z) 330 (M+H)⁺.

Step 2: 4-(3-(2-Chloro-4-fluorophenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(1.1 g, 3.34 mmol) using iron powder (559 mg, 10.0 mmol) and ammoniumchloride (1.8 g, 33.36 mmol) in a mixture of ethanol and water (50 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield732 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.40 (s, 2H), 6.42(d, J=8.4 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 7.33 (t, J=5.7 Hz, 1H),7.43-7.53 (m, 2H), 8.54 (s, 1H), 8.67 (s, 1H).

Intermediate 39 4-(3-(2-Ethylphenyl)pyrazin-2-yl)aniline

Step 1: 2-(2-Chloro-4-fluorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (1.0 g,4.24 mmol) with 2-ethylphenylboronic acid (764 mg, 5.09 mmol) usingsodium carbonate (1.35 g, 12.73 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (151 mg,0.21 mmol) in a mixture of DMSO and water (30 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 1.23 g of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.5 Hz, 3H), 2.33 (q,J=7.5 Hz, 2H), 7.16-7.20 (m, 2H), 7.29 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.9Hz, 1H), 7.60 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.4 Hz, 2H), 8.83 (d, J=5.4Hz, 2H); APCI-MS (m/z) 306 (M+H)⁺.

Step 2: 4-(3-(2-Ethylphenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(1.2 g, 3.93 mmol) using iron powder (658 mg, 11.8 mmol) and ammoniumchloride (2.1 g, 39.3 mmol) in a mixture of ethanol and water (60 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield790 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.5 Hz,3H), 2.26 (q, J=7.5 Hz, 2H), 5.35 (s, 2H), 6.36 (d, J=7.8 Hz, 2H), 7.05(d, J=8.4 Hz, 2H), 7.17-7.34 (m, 4H), 8.51 (s, 1H), 8.61 (s, 1H);APCI-MS (m/z) 276 (M+H)⁺.

Intermediate 404-(3-(4-(2-Methoxyethyl)piperazin-1-yl)pyrazin-2-yl)aniline

Step 1: 2-Chloro-3-(4-(2-methoxyethyl)piperazin-1-yl)pyrazine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(300 mg, 2.01 mmol) with 1-(2-methoxyethyl)piperazine hydrochloride (364mg, 2.01 mmol) in the presence of potassium carbonate (556 mg, 4.03mmol) in acetonitrile (20 mL) as per the procedure described in Step 1of Intermediate 7 to yield 108 mg of the product; ¹H NMR (300 MHz,CDCl₃) δ 2.68-2.73 (m, 6H), 3.37 (s, 3H), 3.52-3.62 (m, 6H), 7.85 (s,1H), 8.09 (s, 1H); ESI-MS (m/z) 257 (M+H)⁺.

Step 2: 4-(3-(4-(2-Methoxyethyl)piperazin-1-yl)pyrazin-2-yl)aniline

The titled compound was prepared by the reaction of Step 1 intermediate(100 mg, 0.39 mmol) with 4-aminophenylboronic acid pinacol ester (102mg, 0.46 mmol) using potassium carbonate (161 mg, 1.17 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (16 mg, 0.02 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 98 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ2.19-2.23 (m, 2H), 2.64-2.72 (m, 6H), 3.32-3.36 (m, 7H), 3.60 (br s,2H), 6.74 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.99 (s, 1H), 8.10(s, 1H).

Intermediate 411-(4-(3-(4-Aminophenyl)pyrazin-2-yl)-3-methylpiperazin-1-yl)ethanone

Step 1: 1-(4-(3-Chloropyrazin-2-yl)-3-methylpiperazin-1-yl)ethanone

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(100 mg, 0.67 mmol) with 1-(3-methylpiperazin-1-yl)ethanone (119 mg,0.84 mmol) in the presence of cesium carbonate (437 mg, 1.34 mmol) inacetonitrile (5.0 mL) as per the procedure described in Step 1 ofIntermediate 7 to yield 46 mg of the product; APCI-MS (m/z) 255 (M+H)⁺.

Step 2:1-(3-Methyl-4-(3-(4-nitrophenyl)pyrazin-2-yl)piperazin-1-yl)ethanone

The titled compound was prepared by the reaction of Step 1 intermediate(200 mg, 0.78 mmol) with 4-nitrophenylboronic acid pinacol ester (235mg, 0.94 mmol) using potassium carbonate (326 mg, 2.36 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (32 mg, 0.04 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 219 mg of the product; APCI-MS (m/z) 342 (M+H)⁺.

Step 3:1-(4-(3-(4-Aminophenyl)pyrazin-2-yl)-3-methylpiperazin-1-yl)ethanone

The titled compound was prepared by the reduction of Step 2 intermediate(200 mg, 0.59 mmol) using iron powder (164 mg, 2.93 mmol) and ammoniumchloride (313 mg, 5.86 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield147 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 0.96, 1.02 (d, J=6.3Hz, 3H, rotamer), 2.04, 2.10 (s, 3H, rotamer), 2.92-2.96 (m, 2H),3.07-3.15 (m, 2H), 3.28-3.39 (m, 2H), 3.65-3.72 (m, 1H), 3.82-4.09 (m,2H), 6.85 (d, J=7.8 Hz, 2H), 7.78 (d, J=5.4 Hz, 2H), 8.04 (s, 1H), 8.13(s, 1H); APCI-MS (m/z) 312 (M+H)⁺.

Intermediate 42 4-(3-(Pyrimidin-5-yl)pyrazin-2-yl)aniline

Step 1: 5-(3-Chloropyrazin-2-yl)pyrimidine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(500 mg, 3.36 mmol) with pyrimidine-5-boronic acid (499 mg, 4.03 mmol)in the presence of potassium carbonate (1.39 g, 10.1 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (137 mg, 0.17 mmol) in a mixture of DMSO andwater (20 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 147 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 8.61 (s, 1H), 8.83 (s, 1H), 9.20 (s, 2H), 9.31 (s, 1H); APCI-MS (m/z)193 (M+H)⁺.

Step 2: 5-(3-(4-Nitrophenyl)pyrazin-2-yl)pyrimidine

The titled compound was prepared by the reaction of Step 1 intermediate(140 mg, 0.73 mmol) with 4-nitrophenylboronic acid pinacol ester (217mg, 0.87 mmol) using potassium carbonate (301 mg, 2.18 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (30 mg, 0.04 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 156 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ7.65 (d, J=8.7 Hz, 2H), 8.25 (d, J=7.2 Hz, 2H), 8.77 (s, 2H), 8.83 (s,2H), 9.22 (s, 1H); APCI-MS (m/z) 280 (M+H)⁺.

Step 3: 4-(3-(Pyrimidin-5-yl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 2 intermediate(150 mg, 0.54 mmol) using iron powder (150 mg, 2.69 mmol) and ammoniumchloride (287 mg, 5.37 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield97 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ 3.23 (br s, 2H), 6.71(d, J=7.8 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 8.60 (d, J=12.9 Hz, 2H), 8.85(s, 2H), 9.15 (s, 1H); APCI-MS (m/z) 250 (M+H)⁺.

Intermediate 43 4-(3-(4-Fluoro-2-methylphenyl)pyrazin-2-yl)aniline

Step 1: 2-(4-Fluoro-2-methylphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (300 mg,1.27 mmol) with 4-fluoro-2-methylphenylboronic acid (294 mg, 1.90 mmol)using potassium carbonate (528 mg, 13.8 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex (52 mg, 0.06 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 223 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 1.98 (s, 3H), 7.01 (t, J=8.1 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 7.21 (t,J=8.1 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H), 8.80 (d,J=5.1 Hz, 2H).

Step 2: 4-(3-(4-Fluoro-2-methylphenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(215 mg, 0.69 mmol) using iron powder (194 mg, 3.47 mmol) and ammoniumchloride (372 mg, 6.95 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield163 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.90 (s, 3H), 5.38(s, 2H), 6.40 (d, J=8.4 Hz, 2H), 7.00-7.10 (m, 4H), 7.21-7.26 (m, 1H),8.53 (s 1H), 8.63 (s, 1H); ESI-MS (m/z) 280 (M+H)+.

Intermediate 44 4-(3-(4-Chlorophenyl)pyridin-4-yl)aniline

Step 1: 3-Bromo-4-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of 3,4-dibromopyridine(1.01 g, 4.26 mmol) with 4-nitrophenylboronic acid pinacol ester (1.06g, 4.26 mmol) using cesium carbonate (2.07 g, 6.39 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (155 mg,0.21 mmol) in a mixture of DMSO and water (20 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 455 mg of theproduct; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d, J=4.8 Hz, 1H), 7.63 (d,J=8.7 Hz, 2H), 8.35 (d, J=8.7 Hz, 2H), 8.64 (d, J=5.1 Hz, 1H), 8.89 (s,1H); ESI-MS (m/z) 281 (M+2H)⁺.

Step 2: 3-(4-Chlorophenyl)-4-(4-nitrophenyl)pyridine

The titled compound was prepared by the reaction of Step 1 intermediate(451 mg, 1.62 mmol) with 4-chlorophenylboronic acid (253 mg, 1.62 mmol)using sodium carbonate (514 mg, 4.85 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (59 mg,0.08 mmol) in a mixture of DMSO and water (10 mL, 4:1) at RT as per theprocedure described in Step 1 of Intermediate 1 to yield 279 mg of theproduct; APCI-MS (m/z) 311 (M+H)⁺.

Step 3: 4-(3-(4-Chlorophenyl)pyridin-4-yl)aniline

The titled compound was prepared by the reduction of Step 2 intermediate(221 mg, 0.71 mmol) using iron powder (119 mg, 2.13 mmol) and ammoniumchloride (380 mg, 7.11 mmol) in a mixture of ethanol and water (10 mL,3:1) as per the procedure described in Step 4 of Intermediate 9 to yield113 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s, 2H), 6.43(d, J=8.1 Hz, 2H), 6.79 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H),7.31-7.38 (m, 3H), 8.42 (s, 1H), 8.49 (d, J=5.4 Hz, 1H); APCI-MS (m/z)281 (M+H)⁺.

Intermediate 45 4-(3-(2,4-Dimethylphenyl)pyrazin-2-yl)aniline

Step 1: 2-(2,4-Dimethylphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (300 mg,1.27 mmol) with 2,4-dimethylphenylboronic acid (286 mg, 1.91 mmol) usingpotassium carbonate (528 mg, 3.81 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (52 mg, 0.06 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 298 mg of the product; ¹H NMR (300 MHz, CDCl₃) δ1.97 (s, 3H), 2.34 (s, 3H), 6.99-7.07 (s, 3H), 7.59 (d, J=8.1 Hz, 2H),8.10 (d, J=8.7 Hz, 2H), 8.68 (s, 2H); APCI-MS (m/z) 306 (M+H)⁺.

Step 2: 4-(3-(2,4-Dimethylphenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(290 mg, 0.95 mmol) using iron powder (265 mg, 4.75 mmol) and ammoniumchloride (508 mg, 9.5 mmol) in a mixture of ethanol and water (24 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield243 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.92 (s, 3H), 2.33(s, 3H), 3.75 (br s, 2H), 6.53 (d, J=8.1 Hz, 2H), 6.96 (s, 1H), 7.02 (d,J=8.1 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.20-7.27 (m, 2H), 8.49 (s, 1H),8.55 (s, 1H); APCI-MS (m/z) 276 (M+H)⁺.

Intermediate 46 4-(3-(2-Fluoro-4-methylphenyl)pyrazin-2-yl)aniline

Step 1: 2-(2-Fluoro-4-methylphenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of Intermediate 11) (300 mg,1.27 mmol) with 2-fluoro-4-methylphenylboronic acid (294 mg, 1.90 mmol)using potassium carbonate (528 mg, 13.8 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (52 mg, 0.06 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 298 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 2.33 (s, 3H), 6.95 (d, J=11.4 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.54(t, J=7.8 Hz, 1H), 6.65 (d, J=8.7 Hz, 2H), 8.18 (d, J=9.0 Hz, 2H), 8.83(s, 2H); ESI-MS (m/z) 310 (M+H)⁺.

Step 2: 4-(3-(2-Fluoro-4-methylphenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(290 mg, 0.94 mmol) using iron powder (262 mg, 4.69 mmol) and ammoniumchloride (501 mg, 9.38 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield163 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.34 (s, 3H), 5.36(s, 2H), 6.42 (d, J=8.1 Hz, 2H), 6.96 (d, J=11.1 Hz, 1H), 7.05-7.10 (m,3H), 7.41 (t, J=7.8 Hz, 1H), 8.53 (s, 1H), 8.61 (s, 1H); ESI-MS (m/z)280 (M+H)⁺.

Intermediate 472-(4-Aminophenyl)-3-(2-chloro-4-fluorophenyl)pyrimidin-4(3H)-one

Step 1:(N)—N′-(2-Chloro-4-fluorophenyl)-N-((dimethylamino)methylene)-4-nitrobenzimidamide

A mixture of 4-nitrobenzonitrile (250 mg, 1.69 mmol),2-chloro-4-fluoroaniline (243 μL, 2.02 mmol) and aluminum chloride (247mg, 1.86 mmol) in THF (10 mL) was heated at 100° C. overnight. Thereaction mixture was quenched with water and concentrated hydrochloricacid before the product was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine and concentrated underreduced pressure. The residue was dissolved in THF (10 mL) and addedDMF-DMA (338 μL, 2.53 mmol) at RT. The mixture was refluxed overnightbefore cooled down to RT and concentrated to yield 537 mg of the crudeproduct which was as such used in the next step.

Step 2: 3-(2-Chloro-4-fluorophenyl)-2-(4-nitrophenyl)pyrimidin-4(3H)-one

To a stirred solution of Step 1 intermediate (537 mg, 1.54 mmol) inethyl acetate (10 mL) was added (trimethylsilyl)ketene (527 mg, 4.62mmol) and the mixture was refluxed overnight. The reaction mixture wascooled to RT and concentrated under reduced pressure. The residue thusobtained was purified by flash column chromatography to afford 236 mg ofthe desired product; ¹H NMR (300 MHz, DMSO-d₆) δ 6.68 (d, J=6.9 Hz, 1H),7.31 (t, J=6.9 Hz, 1H), 7.56 (d, J=5.4 Hz, 1H), 7.64 (d, J=8.7 Hz, 2H),7.75-7.82 (m, 1H), 8.13-8.20 (m, 3H); APCI-MS (m/z) 346 (M+H)⁺.

Step 3: 2-(4-Aminophenyl)-3-(2-chloro-4-fluorophenyl)pyrimidin-4(3H)-one

The titled compound was prepared by the reduction of Step 2 intermediate(151 mg, 0.44 mmol) using iron powder (73 mg, 1.30 mmol) and ammoniumchloride (234 mg, 4.37 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield102 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.59 (s, 2H), 6.34(d, J=7.2 Hz, 2H), 6.43 (d, J=6.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H),7.28-7.32 (m, 1H), 7.50-7.63 (m, 2H), 8.05 (d, J=6.3 Hz, 1H); APCI-MS(m/z) 316 (M+H)⁺.

Intermediate 48 4-(3-(2,4-Dichlorophenyl)pyrazin-2-yl)aniline

Step 1: 2-(2,4-Dichlorophenyl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (300 mg,1.27 mmol) with 2,4-dichlorophenylboronic acid (364 mg, 1.91 mmol) usingpotassium carbonate (528 mg, 3.81 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (52 mg, 0.06 mmol) in a mixture of DMSO andwater (12 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 223 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 7.55-7.68 (m, 5H), 8.20 (d, J=8.7 Hz, 2H), 8.88 (d, J=11.1 Hz, 2H);APCI-MS (m/z) 346 (M+H)⁺.

Step 2: 4-(3-(2,4-Dichlorophenyl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(220 mg, 0.64 mmol) using iron powder (177 mg, 3.18 mmol) and ammoniumchloride (339 mg, 6.36 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield162 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.41 (s, 2H), 6.42(d, J=8.7 Hz, 2H), 7.03 (d, J=7.8 Hz, 2H), 7.51 (s, 2H), 7.64 (s, 1H),8.55 (s, 1H), 8.68 (s, 1H); APCI-MS (m/z) 316 (M+H)⁺.

Intermediate 49(4-(3-(4-Aminophenyl)pyrazin-2-yl)piperazin-1-yl)(cyclopropyl)methanone

Step 1: (4-(3-Chloropyrazin-2-yl)piperazin-1-yl)(cyclopropyl)methanone

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(100 mg, 0.67 mmol) with cyclopropyl(piperazin-1-yl)methanonetrifluoroacetate salt (180 mg, 0.67 mmol) using potassium carbonate (93mg, 0.67 mmol) in acetonitrile (15 mL) at 80° C. as per the proceduredescribed in Step 1 of Intermediate 7 to yield 49 mg of the product; ¹HNMR (300 MHz, CDCl₃) δ 0.78-0.82 (m, 2H), 0.98-1.03 (m, 2H), 1.75-1.79(m, 1H), 3.46-3.550 (m, 4H), 3.80-3.84 (m, 4H), 7.93 (s, 1H), 8.13 (s,1H).

Step 2.(4-(3-(4-Aminophenyl)pyrazin-2-yl)piperazin-1-yl)(cyclopropyl)methanone

The titled compound was prepared by the reaction of Step 1 intermediate(250 mg, 0.93 mmol) with 4-aminophenylboronic acid pinacol ester (246mg, 1.13 mmol) using potassium carbonate (389 mg, 2.81 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (77 mg, 0.09 mmol) in a mixture of DMSO andwater (16 mL, 3:1) as per the procedure described in Step 1 ofIntermediate 1 to yield 198 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 0.68-0.72 (m, 4H), 1.95-1.99 (m, 1H), 3.07-3.12 (m, 4H), 3.51-3.55 (m,2H), 3.70-3.74 (m, 2H), 5.46 (s, 2H), 6.62 (d, J=6.9 Hz, 2H), 7.71 (d,J=6.9 Hz, 2H), 8.02 (s, 1H), 8.12 (s, 1H); APCI-MS (m/z) 324 (M+H)⁺.

Intermediate 503-(4-Aminophenyl)-N-(4-chlorophenyl)-N-methylpyrazin-2-amine

Step 1: 3-Chloro-N-(4-chlorophenyl)pyrazin-2-amine

To a stirred solution of 4-chloroaniline (645 mg, 5.06 mmol) in THF (5.0mL) was added sodium bis(trimethylsilyl)amide (1M, 5.0 mL, 5.06 mmol) at0° C. and the mixture was stirred for 30 min at the same temperature. Asolution of 2,3-dichloropyrazine (503 mg, 3.38 mmol) in THF (5.0 mL) wasslowly added to the reaction mixture at 0° C. The mixture was stirredovernight at RT. The reaction mixture was quenched with aqueous ammoniumchloride solution (10 mL) and diluted with water (10 mL). The aqueousmixture was extracted with ethyl acetate (2×20 mL). The combined organiclayers were washed with brine (25 mL) and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residueobtained was purified by silica gel column chromatography to yield 63 mgof the titled product; ¹H NMR (300 MHz, DMSO-d₆) δ 7.36 (d, J=8.7 Hz,2H), 7.72 (d, J=8.7 Hz, 2H), 7.84 (s, 1H), 8.13 (s, 1H), 8.92 (s, 1H);APCI-MS (m z) 240 (M+H)+, 242 (M+2H)+.

Step 2: 3-Chloro-N-(4-chlorophenyl)-N-methylpyrazin-2-amine

To a stirred suspension of Step 1 intermediate (1.06 g, 4.43 mmol) inDMF (5.0 mL) was added sodium hydride (60% w/w, 213 mg, 5.32 mmol) at 0°C. and the mixture was stirred for 10-15 min at RT. Methyl iodide (333μL, 5.32 mmol) was added to the reaction mixture and stirred for 2 h atRT. The reaction mixture was quenched with aqueous ammonium chloridesolution (20 mL) and diluted with water (10 mL). The aqueous mixture wasextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with brine (30 mL) and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to yield 723 mg of the titledproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 3.38 (s, 3H), 7.02 (d, J=9.0 Hz,2H), 7.35 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 8.43 (s, 1H); ESI-MS (m z)254 (M)⁺.

Step 3: 3-(4-Aminophenyl)-N-(4-chlorophenyl)-N-methylpyrazin-2-amine

The titled compound was prepared by the reaction of Step 2 intermediate(203 mg, 0.78 mmol) with 4-aminophenylboronic acid (280 mg, 0.96 mmol)using sodium carbonate (254 mg, 2.39 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (59 mg,0.08 mmol) in a mixture of DMSO and water (10 mL, 4:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 143 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 3.22 (s, 3H), 5.40 (br s, 2H), 6.43(d, J=8.1 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.7 Hz, 2H), 7.40(d, J=8.4 Hz, 2H), 8.23 (s, 1H), 8.38 (s, 1H); APCI-MS (m/z) 311 (M+H)⁺.

Intermediate 51 3-(4-Aminophenyl)-N-benzyl-N-methylpyrazin-2-amine

Step 1: N-Benzyl-3-chloropyrazin-2-amine

To a stirred solution of 2,3-dichloropyrazine (1.0 g, 6.71 mmol) andbenzyl amine (880 μL, 8.05 mmol) in 1,4-dioxane (20 mL) was addedtriethylamine (1.4 mL, 10.07 mmol) and the mixture was heated overnightat 100° C. The reaction mixture was cooled to RT and diluted with ethylacetate (50 mL). The organic extract was washed with 1N HCl (50 mL)followed by brine (30 mL). The organic layer was concentrated underreduced pressure and the residue thus obtained was purified by silicagel column chromatography to yield 613 mg of the titled product; ¹H NMR(300 MHz, DMSO-d₆) δ 4.57 (d, J=6.3 Hz, 2H), 7.19-7.31 (m, 5H), 7.55 (s,1H), 7.65-7.72 (m, 1H), 7.96 (s, 1H); APCI-MS (m/z) 220 (M+H)⁺.

Step 2: N-Benzyl-3-chloro-N-methylpyrazin-2-amine

The titled compound was prepared by the reaction of step 1 intermediate(599 mg, 2.72 mmol) with methyl iodide (205 μL, 3.27 mmol) in thepresence of sodium hydride (60% w/w, 130 mg, 3.27 mmol) as per theprocedure described in Step 2 of Intermediate 50 to yield 573 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (s, 3H), 4.66 (s, 2H),7.25-7.38 (m, 5H), 7.91 (s, 1H), 8.21 (s, 1H); APCI-MS (m/z) 234 (M+H)+.

Step 3: 3-(4-Aminophenyl)-N-benzyl-N-methylpyrazin-2-amine

The titled compound was prepared by the reaction of Step 2 intermediate(333 mg, 1.42 mmol) with 4-aminophenylboronic acid pinacol ester (498mg, 1.71 mmol) using sodium carbonate (452 mg, 4.27 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (52 mg,0.07 mmol) in a mixture of DMSO and water (10 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 270 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (s, 3H), 4.38 (s, 2H), 5.41(s, 2H), 6.60 (d, J=8.4 Hz, 2H), 7.10 (d, J=7.2 Hz, 2H), 7.22-7.28 (m,3H), 7.53 (d, J=8.1 Hz, 2H), 7.96 (s, 1H), 8.03 (s, 1H).

Intermediate 52 3-(4-Aminophenyl)-N-benzylpyrazin-2-amine

The titled compound was prepared by the reaction ofN-benzyl-3-chloropyrazin-2-amine (Step 1 of Intermediate 51) (203 mg,0.92 mmol) with 4-aminophenylboronic acid pinacol ester (323 mg, 1.10mmol) using sodium carbonate (294 mg, 2.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (66 mg,0.09 mmol) in a mixture of DMSO and water (8.0 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 152 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 4.51 (d, J=6.0 Hz, 2H), 5.46 (br s,2H), 6.67 (d, J=8.1 Hz, 2H), 6.74-6.78 (m, 1H), 7.16-7.20 (m, 1H),7.28-7.32 (m, 4H), 7.40 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 7.79 (s, 1H);ESI-MS (m/z) 277 (M+H)⁺.

Intermediate 53 3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

Step 1: 3-Chloro-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(2.3 g, 15.4 mmol) with DL-1-phenylethanamine (2.16 mL, 17.0 mmol) usingN,N-diisopropylethylamine (7.9 mL, 46 mmol) in 1,4-dioxane (40 mL) asper the procedure described in Step 1 of Intermediate 51 to yield 353 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.53 (d, J=6.9 Hz, 3H),5.19-5.23 (m, 1H), 7.17-7.32 (m, 3H), 7.39 (d, J=7.5 Hz, 2H), 7.53 (s,1H), 7.94 (s, 1H), 8.56 (s, 1H).

Step 2: 3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(206 mg, 0.88 mmol) with 4-aminophenylboronic acid pinacol ester (308mg, 1.06 mmol) using sodium carbonate (280 mg, 2.64 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (63 mg,0.08 mmol) in a mixture of DMSO and water (10 mL, 4:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 105 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.44 (d, J=5.4 Hz, 3H), 5.11-5.12(m, 1H), 5.55 (s, 2H), 6.06-6.10 (m, 1H), 6.67 (d, J=7.8 Hz, 2H),7.19-7.41 (m, 6H), 7.72 (s, 1H), 7.77 (s, 1H).

Intermediate 54 (R)-3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

Step 1: (R)-3-Chloro-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(503 mg, 3.37 mmol) with (R)-(+)-α-methylbenzylamine (430 μL, 3.37 mmol)using potassium carbonate (1.4 g, 10.1 mmol) in DMF (10 mL) as per theprocedure described in Step 1 of Intermediate 51 to yield 243 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.53 (d, J=6.9 Hz, 3H), 5.17-5.23(m, 1H), 7.17-7.32 (m, 4H), 7.39 (d, J=7.2 Hz, 2H), 7.53 (s, 1H), 7.94(s, 1H); APCI-MS (m/z) 234 (M+H)⁺.

Step 2: (R)-3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(232 mg, 0.99 mmol) with 4-aminophenylboronic acid pinacol ester (435mg, 1.49 mmol) using sodium carbonate (370 mg, 3.49 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (71 mg,0.09 mmol) in a mixture of DMSO and water (10 mL, 4:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 210 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (d, J=6.6 Hz, 3H), 5.12-5.18(m, 1H), 5.46 (s, 2H), 6.09 (d, J=6.9 Hz, 1H), 6.67 (d, J=8.1 Hz, 2H),7.18 (d, J=7.2 Hz, 1H), 7.28 (t, J=7.2 Hz, 2H), 7.34-7.44 (m, 4H), 7.72(s, 1H), 7.77 (s, 1H); APCI-MS (m/z) 291 (M+H)⁺.

Intermediate 55(R)-3-(4-Aminophenyl)-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

Step 1: (R)-3-Chloro-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of(R)-3-chloro-N-(1-phenylethyl)pyrazin-2-amine (Step 1 of Intermediate54) (503 mg, 2.15 mmol) with methyl iodide (180 μL, 2.79 mmol) in thepresence of sodium hydride (60% w/w, 103 mg, 2.58 mmol) in DMF (10 mL)as per the procedure described in Step 2 of Intermediate 50 to yield 323mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.56 (d, J=6.9 Hz, 3H),2.66 (s, 3H), 5.40-5.44 (m, 1H), 7.30-7.36 (m, 5H), 7.93 (s, 1H), 8.31(s, 1H); ESI-MS (m/z) 248 (M+H)⁺.

Step 2: (R)-3-(4-Aminophenyl)-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 2 intermediate(302 mg, 1.22 mmol) with 4-aminophenylboronic acid pinacol ester (530mg, 1.82 mmol) using sodium carbonate (388 mg, 3.65 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (44 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 183 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (d, J=6.9 Hz, 3H), 2.38 (s,3H), 5.22-5.26 (m, 1H), 5.36 (s, 2H), 6.60 (d, J=8.4 Hz, 2H), 7.12 (d,J=5.7 Hz, 2H), 7.19-7.28 (m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.95 (s, 1H),8.02 (s, 1H); APCI-MS (m/z) 305 (M+H)⁺.

Intermediate 56 (S)-3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

Step 1: (S)-3-Chloro-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(2.0 g, 13.4 mmol) with (S)-(−)-α-methylbenzylamine (4.56 mL, 20.13mmol) using potassium carbonate (5.56 g, 40.2 mmol) in DMF (30 mL) asper the procedure described in Step 1 of Intermediate 51 to yield 2.3 gof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.53 (d, J=6.9 Hz, 3H),5.16-5.23 (m, 1H), 7.17-7.32 (m, 4H), 7.39 (d, J=7.5 Hz, 2H), 7.53 (s,1H), 7.94 (s, 1H); APCI-MS (m/z) 234 (M+H)⁺.

Step 2: (S)-3-(4-Aminophenyl)-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(250 mg, 1.07 mmol) with 4-aminophenylboronic acid pinacol ester (374mg, 1.28 mmol) using sodium carbonate (340 mg, 3.20 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (38 mg,0.05 mmol) in a mixture of DMSO and water (10 mL, 4:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 190 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (d, J=6.6 Hz, 3H), 5.12-5.16(m, 1H), 5.45 (s, 2H), 6.12 (d, J=6.9 Hz, 1H), 6.67 (d, J=8.7 Hz, 2H),7.19 (d, J=7.8 Hz, 1H), 7.28 (t, J=8.7 Hz, 2H), 7.35-7.44 (m, 3H), 7.72(s, 1H), 7.78 (s, 1H); APCI-MS (m/z) 291 (M+H)⁺.

Intermediate 57(S)-3-(4-Aminophenyl)-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

Step 1: (S)-3-Chloro-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of(S)-3-chloro-N-(1-phenylethyl)pyrazin-2-amine (Step 1 of Intermediate56) (503 mg, 2.15 mmol) with methyl iodide (180 μL, 2.79 mmol) in thepresence of sodium hydride (60% w/w, 103 mg, 2.58 mmol) in DMF (10 mL)as per the procedure described in Step 2 of Intermediate 50 to yield 402mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.53 (d, J=6.9 Hz, 3H),2.63 (s, 3H), 5.37-5.42 (m, 1H), 7.28-7.33 (m, 5H), 7.91 (s, 1H), 8.19(s, 1H); APCI-MS (m/z) 248 (M+H)⁺.

Step 2: (S)-3-(4-Aminophenyl)-N-methyl-N-(1-phenylethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 2 intermediate(302 mg, 1.22 mmol) with 4-aminophenylboronic acid pinacol ester (425mg, 1.46 mmol) using sodium carbonate (388 mg, 3.65 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (44 mg,0.06 mmol) in a mixture of DMSO and water (10 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 230 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (d, J=6.9 Hz, 3H), 2.38 (s,3H), 5.22-5.28 (m, 1H), 5.37 (s, 2H), 6.60 (d, J=8.1 Hz, 2H), 7.12 (d,J=6.9 Hz, 2H), 7.20-7.28 (m, 3H), 7.50 (d, J=8.4 Hz, 2H), 7.95 (s, 1H),8.02 (s, 1H); ESI-MS (m/z) 305 (M+H)⁺.

Intermediate 58(S)-3-(4-Aminophenyl)-N-(1-(4-chlorophenyl)ethyl)pyrazin-2-amine

Step 1: (S)-3-Chloro-N-(1-(4-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(320 mg, 2.15 mmol) with (S)-1-(4-chlorophenyl)ethanamine (456 μL, 3.22mmol) using potassium carbonate (890 mg, 6.44 mmol) in DMF (10 mL) asper the procedure described in Step 1 of Intermediate 51 to yield 243 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.49 (d, J=7.2 Hz, 3H),5.13-5.17 (m, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 7.52(s, 1H), 7.91 (s, 1H), 8.54 (s, 1H); APCI-MS (m/z) 269 (M+H)⁺.

Step 2: (S)-3-(4-Aminophenyl)-N-(1-(4-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(253 mg, 0.94 mmol) with 4-aminophenylboronic acid pinacol ester (330mg, 1.13 mmol) using sodium carbonate (300 mg, 2.83 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (67 mg,0.09 mmol) in a mixture of DMSO and water (10 mL, 4:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 162 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.43 (d, J=6.9 Hz, 3H), 5.08-5.12(m, 1H), 5.45 (s, 2H), 6.24 (d, J=6.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H),7.18 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H),7.73 (d, J=7.5 Hz, 2H), 8.31 (s, 1H); APCI-MS (m/z) 325 (M+H)⁺.

Intermediate 59(S)-3-(4-Aminophenyl)-N-(1-(3-chlorophenyl)ethyl)pyrazin-2-amine

Step 1: (S)—N-(1-(3-Chlorophenyl)ethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (101 mg,0.43 mmol) with (S)-1-(3-chlorophenyl)ethanamine hydrochloride (82 mg,0.43 mmol) using cesium fluoride (268 mg, 1.71 mmol) in DMSO (6.0 mL) asper the procedure described in Step 1 of Intermediate 51 to yield 106 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (d, J=6.6 Hz, 3H),5.17-5.21 (m, 1H), 6.95-6.99 (m, 1H), 7.23-7.35 (m, 3H), 7.45 (s, 1H),7.88 (s, 1H), 8.02 (d, J=9.6 Hz, 3H), 8.37 (d, J=8.7 Hz, 2H).

Step 2: (S)-3-(4-Aminophenyl)-N-(1-(3-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(101 mg, 0.28 mmol) using iron powder (48 mg, 0.85 mmol) and ammoniumchloride (152 mg, 2.85 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield79 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (d, J=6.6 Hz,3H), 5.08-5.12 (m, 1H), 5.44 (s, 2H), 6.28-6.33 (m, 1H), 6.65-7.69 (m,2H), 7.21-7.32 (m, 3H), 7.41-7.45 (m, 3H), 7.74 (d, J=7.8 Hz, 2H)

Intermediate 60(S)-3-(4-Aminophenyl)-N-(1-(4-chlorophenyl)ethyl)-N-methylpyrazin-2-amine

Step 1: (S)-3-Chloro-N-(1-(4-chlorophenyl)ethyl)-N-methylpyrazin-2-amine

The titled compound was prepared by the reaction of(S)-3-Chloro-N-(1-(4-chlorophenyl)ethyl)pyrazin-2-amine (Step 1 ofIntermediate 51) (371 mg, 1.38 mmol) with methyl iodide (130 μL, 2.08mmol) in the presence of sodium hydride (60% w/w, 83 mg, 2.08 mmol) asper the procedure described in Step 2 of Intermediate 50 to yield 352 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.54 (d, J=6.9 Hz, 3H), 2.66(s, 3H), 5.35-5.40 (m, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz,2H), 7.94 (s, 1H), 8.22 (s, 1H); APCI-MS (m/z) 283 (M+H)+.

Step 2:(S)-3-(4-Aminophenyl)-N-(1-(4-chlorophenyl)ethyl)-N-methylpyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(341 mg, 1.20 mmol) with 4-aminophenylboronic acid pinacol ester (422mg, 1.45 mmol) using sodium carbonate (381 mg, 3.60 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (43 mg,0.06 mmol) in DMSO (10 mL) as per the procedure described in Step 1 ofIntermediate 1 to yield 162 mg of the product ¹H NMR (300 MHz, DMSO-d₆)δ 1.40 (d, J=6.9 Hz, 3H), 2.36 (s, 3H), 5.25-5.28 (m, 1H), 5.36 (s, 2H),6.58 (d, J=7.8 Hz, 2H), 7.14 (d, J=7.8 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H),7.46 (d, J=7.8 Hz, 2H), 7.95 (s, 1H), 8.02 (s, 1H); APCI-MS (m/z) 338(M+H)+.

Intermediate 61(S)-3-(4-Aminophenyl)-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

Step 1: (S)—N-(1-(2-Chlorophenyl)ethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (202 mg,0.86 mmol) with (S)-1-(2-chlorophenyl)ethanamine hydrochloride (198 mg,1.03 mmol) using cesium fluoride (390 mg, 2.57 mmol) in DMSO (8.0 mL) asper the procedure described in Step 1 of Intermediate 51 to yield 219 mgof the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (d, J=6.9 Hz, 3H),5.42-5.49 (m, 1H), 7.05 (d, J=8.7 Hz, 1H), 7.19-7.26 (m, 1H), 7.38 (d,J=8.4 Hz, 1H), 7.48 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.97 (s, 1H), 8.03(d, J=8.7 Hz, 3H), 8.37 (d, J=8.7 Hz, 2H).

Step 2: (S)-3-(4-Aminophenyl)-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(192 mg, 0.54 mmol) using iron powder (90 mg, 1.62 mmol) and ammoniumchloride (290 mg, 5.41 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield140 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.43 (d, J=6.9 Hz,3H), 5.37-5.45 (m, 1H), 5.47 (s, 2H), 6.33 (d, J=6.9 Hz, 1H), 6.68 (d,J=8.4 Hz, 2H), 7.19-7.26 (m, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.73 (d, J=5.1 Hz, 2H); APCI-MS (m/z) 325 (M+H)⁺.

Intermediate 62(S)-3-(4-Aminophenyl)-N-(1-(4-fluoro-2-methylphenyl)ethyl)pyrazin-2-amine

Step 1:(S)—N-(1-(4-Fluoro-2-methylphenyl)ethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (S)-1-(4-fluoro-2-methylphenyl)ethanamine hydrochloride(197 mg, 1.03 mmol) using cesium fluoride (523 mg, 3.44 mmol) in DMSO(10 mL) as per the procedure described in Step 1 of Intermediate 51 toyield 190 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (d, J=7.5Hz, 3H), 2.42 (s, 3H), 5.26-5.30 (m, 1H), 6.88-6.95 (m, 3H), 7.38-7.45(m, 1H), 7.85 (s, 1H), 7.95-8.01 (m, 3H), 8.36 (d, J=8.7 Hz, 2H); ESI-MS(m/z) 353 (M+H)+.

Step 2:(S)-3-(4-Aminophenyl)-N-(1-(4-fluoro-2-methylphenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(181 mg, 0.51 mmol) using iron powder (86 mg, 1.54 mmol) and ammoniumchloride (275 mg, 5.14 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield130 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (d, J=6.6 Hz,3H), 2.38 (s, 3H), 5.18-5.22 (m, 1H), 5.47 (s, 2H), 6.16 (d, J=7.8 Hz,1H), 6.64 (d, J=8.4 Hz, 2H), 6.91-6.95 (m, 2H), 7.39 (d, J=8.1 Hz, 3H),7.69 (s, 1H), 7.75 (s, 1H); APCI-MS (m/z) 323 (M+H)⁺.

Intermediate 63(S)-3-(4-Aminophenyl)-N-(1-(2,4-dimethylphen)ethyl)pyrazin-2-amine

Step 1:(S)—N-(1-(2,4-Dimethylphenyl)ethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (S)-1-(2,4-dimethylphenyl)ethanamine hydrochloride (176mg, 0.95 mmol) using cesium fluoride (523 mg, 3.44 mmol) in DMSO (8.0mL) as per the procedure described in Step 1 of Intermediate 51 to yield216 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.36 (d, J=6.3 Hz,3H), 2.19 (s, 3H), 2.36 (s, 3H), 5.26-5.30 (m, 1H), 6.82-6.92 (m, 3H),7.26 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.96 (d, J=8.7 Hz, 3H), 8.36 (d,J=8.4 Hz, 2H); APCI-MS (m/z) 349 (M+H)⁺.

Step 2:(S)-3-(4-Aminophenyl)-N-(1-(2,4-dimethylphenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(209 mg, 0.60 mmol) using iron powder (100 mg, 1.80 mmol) and ammoniumchloride (320 mg, 5.99 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield140 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (d, J=6.6 Hz,3H), 2.19 (s, 3H), 2.33 (s, 3H), 5.20-5.24 (m, 1H), 5.56 (br s, 2H),5.97-6.02 (m, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.92 (s, 2H), 7.23 (d, J=7.8Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.70 (s, 1H), 7.78 (s, 1H); APCI-MS(m/z) 319 (M+H)⁺.

Intermediate 64(S)-3-(4-Aminophenyl)-N-(1-(2-chloro-4-fluorophenyl)ethyl)pyrazin-2-amine

Step 1:(S)—N-(1-(2-Chloro-4-fluorophenyl)ethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (S)-1-(2-chloro-4-fluorophenyl)ethanamine hydrochloride(217 mg, 1.03 mmol) using cesium fluoride (524 mg, 3.44 mmol) in DMSO(8.0 mL) as per the procedure described in Step 1 of Intermediate 51 toyield 103 mg of the product. The product was as such taken for the nextstep without characterization.

Step 2:(S)-3-(4-Aminophenyl)-N-(1-(2-chloro-4-fluorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(98 mg, 0.26 mmol) using iron powder (44 mg, 0.79 mmol) and ammoniumchloride (140 mg, 2.63 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield62 mg of the product. The product was as such taken for the next stepwithout characterization.

Intermediate 65 3-(4-Aminophenyl)-N-(cyclohexylmethyl)pyrazin-2-amine

Step 1: N-(Cyclohexylmethyl)-3-(4-nitrophenyl)pyrazin-2-amine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with cyclohexylmethanamine (146 mg, 1.29 mmol) using cesiumfluoride (392 mg, 2.58 mmol) in DMSO (8.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 121 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.95 (m, 2H), 1.07-1.17 (m, 3H),1.51-1.80 (m, 6H), 3.14 (t, J=6.6 Hz, 2H), 6.64-6.68 (m, 1H), 7.84 (s,1H), 7.90 (d, J=8.7 Hz, 2H), 8.05 (s, 1H), 8.33 (d, J=8.1 Hz, 2H);APCI-MS (m/z) 311 (M−H)−.

Step 2: 3-(4-Aminophenyl)-N-(cyclohexylmethyl)pyrazin-2-amine

The titled compound was prepared by the reduction of Step 1 intermediate(115 mg, 0.37 mmol) using iron powder (62 mg, 1.10 mmol) and ammoniumchloride (197 mg, 3.68 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield84 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 0.88-0.93 (m, 3H),1.12-1.18 (m, 3H), 1.60-1.76 (m, 5H), 3.12 (t, J=5.7 Hz, 2H), 5.42 (s,2H), 6.02-6.06 (m, 1H), 6.64 (d, J=8.4 Hz, 2H), 7.33 (d, J=9.0 Hz, 2H),7.69 (s, 1H), 7.82 (s, 1H); ESI-MS (m/z) 283 (M+H)⁺.

Intermediate 66(S)-3-(4-Amino-3-fluorophenyl)-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

Step 1: (S)-3-Chloro-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(130 mg, 0.87 mmol) with (S)-1-(2-chlorophenyl)ethanamine hydrochloride(250 mg, 1.31 mmol) using cesium fluoride (530 mg, 3.48 mmol) in DMSO(8.0 mL) as per the procedure described in Step 1 of Intermediate 51 toyield 159 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.51 (d, J=6.9Hz, 3H), 5.42-5.47 (m, 1H), 7.21-7.30 (m, 3H), 7.37-7.42 (m, 2H),7.48-7.56 (m, 2H), 7.92 (s, 1H).

Step 2:(S)-3-(4-Amino-3-fluorophenyl)-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of Step 1 intermediate(151 mg, 0.56 mmol) with 4-amino-3-fluorophenylboronic acid pinacolester (160 mg, 0.68 mmol) using sodium carbonate (180 mg, 1.69 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (46 mg,0.06 mmol) in a mixture of DMSO and water (8.0 mL, 3:1) as per theprocedure described in Step 1 of Intermediate 1 to yield 159 mg of theproduct; ¹H NMR (300 MHz DMSO-d₆) δ 1.43 (d, J=6.6 Hz, 3H), 3.94 (s,1H), 5.38-5.42 (m, 1H), 5.51 (s, 2H), 6.60 (d, J=6.6 Hz, 1H), 6.83-6.91(m, 1H), 7.19-7.25 (m, 2H), 7.36-7.41 (m, 2H), 7.46 (d, J=5.7 Hz, 1H),7.72-7.78 (m, 2H); ESI-MS (m/z) 343 (M+H)⁺.

Intermediate 67(S)-3-(4-Amino-2-fluorophenyl)-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine

The titled compound was prepared by the reaction of(S)-3-chloro-N-(1-(2-chlorophenyl)ethyl)pyrazin-2-amine (Step 1 ofIntermediate 66) (206 mg, 0.77 mmol) with 4-amino-2-fluorophenylboronicacid pinacol ester (273 mg, 1.15 mmol) using sodium carbonate (244 mg,2.30 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.08 mmol) in a mixture of DMSO and water (10 mL, 3:1) asper the procedure described in Step 1 of Intermediate 1 to yield 149 mgof the product; ¹H NMR (300 MHz DMSO-d₆) δ 1.37 (d, J=6.9 Hz, 3H),5.38-5.43 (m, 1H), 5.69 (s, 2H), 6.27 (d, J=6.6 Hz, 1H), 6.39-6.51 (m,2H), 7.09-7.23 (m, 3H), 7.35 (d, J=6.0 Hz, 1H), 7.41-7.45 (m, 1H), 7.71(s, 1H), 7.81 (s, 1H); ESI-MS (m/z) 343 (M+H)⁺.

Intermediate 68 4-(3-(Benzyloxy)pyrazin-2-yl)aniline

Step 1: 2-(Benzyloxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (109 mg,0.46 mmol) with benzyl alcohol (72 μL, 0.69 mmol) using cesium fluoride(280 mg, 1.84 mmol) in DMSO (8.0 mL) as per the procedure described inStep 1 of Intermediate 51 to yield 96 mg of the product; ¹H NMR (300MHz, DMSO-d₆) δ 5.52 (s, 2H), 7.36-7.40 (m, 3H), 7.45-7.49 (m, 2H),8.31-8.35 (m, 5H), 8.44 (s, 1H); APCI-MS (m/z) 308 (M+H)+.

Step 2: 4-(3-(Benzyloxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(89 mg, 0.29 mmol) using iron powder (49 mg, 0.87 mmol) and ammoniumchloride (155 mg, 2.89 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield72 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.46 (s, 2H), 5.53 (s,2H), 6.58 (d, J=8.1 Hz, 2H), 7.36-7.41 (m, 3H), 7.43-7.48 (m, 2H), 7.85(d, J=8.4 Hz, 2H), 8.01 (s, 1H), 8.20 (s, 1H); APCI-MS (m/z) 278 (M+H)⁺.

Intermediate 69 4-(3-(1-Phenylethoxy)pyrazin-2-yl)aniline

Step 1: 2-(4-Nitrophenyl)-3-(1-phenylethoxy)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with 1-phenylethanol (156 μL, 1.29 mmol) using cesiumfluoride (392 mg, 2.58 mmol) in DMSO (10 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 196 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz, 3H), 6.28-6.32 (m, 1H),7.26-7.34 (m, 3H), 7.42 (d, J=6.9 Hz, 2H), 8.24 (s, 1H), 8.35 (s, 5H);APCI-MS (m/z) 322 (M+H)+.

Step 2: 4-(3-(1-Phenylethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(189 mg, 0.59 mmol) using iron powder (99 mg, 1.76 mmol) and ammoniumchloride (315 mg, 5.88 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield141 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.63 (d, J=6.3 Hz,3H), 5.67 (br s, 2H), 6.25 (d, J=6.3 Hz, 1H), 6.64 (d, J=8.7 Hz, 2H),7.24-7.43 (m, 5H), 7.92 (d, J=8.4 Hz, 3H), 8.14 (s, 1H); APCI-MS (m/z)292 (M+H)⁺.

Intermediate 70 4-(3-((2-Chloro-4-fluorobenzyl)oxy)pyrazin-2-yl)aniline

Step 1: 2-((2-Chloro-4-fluorobenzyl)oxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with 2-chloro-4-fluorobenzylalcohol (152 μL, 0.94 mmol) usingcesium fluoride (261 mg, 1.72 mmol) in DMSO (10 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 261 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 5.56 (s, 2H), 7.25-7.29 (m, 1H), 7.53 (d,J=9.3 Hz, 1H), 7.62-7.68 (m, 1H), 8.28-8.37 (m, 5H), 8.46 (s, 1H);APCI-MS (m/z) 360 (M+H)⁺.

Step 2: 4-(3-((2-Chloro-4-fluorobenzyl)oxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(249 mg, 0.69 mmol) using iron powder (116 mg, 2.08 mmol) and ammoniumchloride (370 mg, 6.92 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield120 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.49 (s, 2H), 5.58(br s, 2H), 6.58 (d, J=8.1 Hz, 2H), 7.25-7.29 (m, 1H), 7.56 (d, J=8.7Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 8.03 (s, 1H),8.23 (s, 1H); APCI-MS (m/z) 330 (M+H)⁺.

Intermediate 71 (R)-4-(3-(1-Phenylethoxy)pyrazin-2-yl)aniline

Step 1: (R)-2-(4-nitrophenyl)-3-(1-phenylethoxy)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (R)-1-phenylethanol (109 μL, 0.95 mmol) using cesiumfluoride (326 mg, 2.15 mmol) in DMSO (8.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 211 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz, 3H), 6.29 (d, J=6.3 Hz,1H), 7.23-7.36 (m, 3H), 7.42 (d, J=6.9 Hz, 2H), 8.24 (s, 1H), 8.35 (s,5H).

Step 2: (R)-4-(3-(1-Phenylethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(204 mg, 0.70 mmol) using iron powder (118 mg, 2.10 mmol) and ammoniumchloride (374 mg, 70.0 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield142 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz,3H), 5.56 (br s, 2H), 6.25 (d, J=6.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 2H),7.24-7.44 (m, 5H), 7.89-7.93 (m, 3H), 8.14 (s, 1H); APCI-MS (m/z) 292(M+H)⁺.

Intermediate 72 (S)-4-(3-(1-Phenyl ethoxy)pyrazin-2-yl)aniline

Step 1: (S)-2-(4-nitrophenyl)-3-(1-phenylethoxy)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (S)-1-phenylethanol (114 μL, 0.91 mmol) using cesiumfluoride (325 mg, 2.15 mmol) in DMSO (8.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 130 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (d, J=6.3 Hz, 3H), 6.29-6.33 (m, 1H),7.28 (d, J=6.9 Hz, 1H), 7.35 (t, J=6.9 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H),8.26 (s, 1H), 8.37 (s, 5H); APCI-MS (m/z) 322 (M+H)⁺.

Step 2: (S)-4-(3-(1-Phenylethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(120 mg, 0.41 mmol) using iron powder (69 mg, 1.23 mmol) and ammoniumchloride (220 mg, 4.11 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield87 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.63 (d, J=6.3 Hz,3H), 5.56 (s, 2H), 6.23-6.27 (m, 1H), 6.63 (d, J=9.0 Hz, 2H), 7.26 (d,J=6.9 Hz, 1H), 7.34 (t, J=7.2 Hz, 2H), 7.42 (d, J=7.2 Hz, 2H), 7.89-7.93(m, 3H), 8.14 (s, 1H); APCI-MS (m/z) 292 (M+H)⁺.

Intermediate 73 4-(3-(1-(2-Cyclopropylphenyl)ethoxy)pyrazin-2-yl)aniline

Step 1: 2-(1-(2-Cyclopropylphenyl)ethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (400 mg,1.69 mmol) with 1-(2-cyclopropylphenyl)ethanol (275 mg, 1.69 mmol) usingcesium fluoride (770 mg, 5.07 mmol) in DMSO (15 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 260 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 0.59-0.63 (m, 1H), 0.73-0.77 (m, 1H),0.89-0.94 (m, 2H), 1.67 (d, J=6.3 Hz, 3H), 2.09-2.13 (m, 1H), 6.76-6.81(m, 1H), 7.00-7.03 (m, 1H), 7.11-7.15 (m, 2H), 7.31-7.35 (m, 1H), 8.22(s, 1H), 8.33-8.37 (m, 5H); APCI-MS (m/z) 362 (M+H)⁺.

Step 2: 4-(3-(1-(2-Cyclopropylphenyl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(200 mg, 0.55 mmol) using iron powder (92 mg, 1.65 mmol) and ammoniumchloride (296 mg, 5.53 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield140 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 0.60-0.64 (m, 1H),0.74-0.78 (m, 1H), 0.90-0.95 (m, 2H), 1.64 (d, J=6.3 Hz, 3H), 2.11-2.15(m, 1H), 5.55 (s, 2H), 6.64 (d, J=8.7 Hz, 2H), 6.72-6.76 (m, 1H),7.01-7.05 (m, 1H), 7.11-7.17 (m, 2H), 7.34-7.38 (m, 1H), 7.89-7.96 (m,3H), 8.12 (s, 1H); APCI-MS (m/z) 332 (M+H)⁺.

Intermediate 74 4-(3-(1-Phenylcyclopropoxy)pyrazin-2-yl)aniline

Step 1: 2-(4-Nitrophenyl)-3-(1-phenylcyclopropoxy)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (151 mg,0.64 mmol) with 1-phenylcyclopropanol (129 mg, 0.96 mmol) using cesiumfluoride (389 mg, 2.56 mmol) in DMSO (10 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 76 mg of the product; ¹HNMR (300 MHz, DMSO-d₆) δ 1.39-1.43 (m, 2H), 1.49-1.53 (m, 2H), 7.20-7.28(m, 5H), 8.21 (s, 1H), 8.30-8.41 (m, 5H).

Step 2: 4-(3-(1-Phenylcyclopropoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(72 mg, 0.22 mmol) using iron powder (36 mg, 0.64 mmol) and ammoniumchloride (116 mg, 2.16 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield65 mg of the product. The product was as such taken for the next stepwithout characterization.

Intermediate 75 (R)-4-(3-(1-(2-chlorophenyl)ethoxy)pyrazin-2-yl)aniline

Step 1: (R)-2-(1-(2-Chlorophenyl)ethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (300 mg,1.27 mmol) with (R)-1-(2-chlorophenyl)ethanol (209 mg, 1.33 mmol) usingcesium fluoride (580 mg, 3.82 mmol) in DMSO (10 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 374 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (d, J=6.3 Hz, 3H), 6.50-6.54 (m, 1H),7.29-7.36 (m, 3H), 7.44-7.49 (m, 2H), 8.25 (s, 1H), 8.38 (s, 4H).

Step 2: (R)-4-(3-(1-(2-chlorophenyl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(366 mg, 1.03 mmol) using iron powder (172 mg, 3.08 mmol) and ammoniumchloride (550 mg, 10.28 mmol) in a mixture of ethanol and water (25 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield230 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz,3H), 5.58 (s, 2H), 6.45-6.50 (m, 1H), 6.64 (d, J=8.7 Hz, 2H), 7.29-7.32(m, 2H), 7.43-7.47 (m, 2H), 7.90-7.95 (m, 3H), 8.15 (s, 1H).

Intermediate 76 (S)-4-(3-(1-(2-chlorophenyl)ethoxy)pyrazin-2-yl)aniline

Step 1: (S)-2-(1-(2-Chlorophenyl)ethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (300 mg,1.27 mmol) with (S)-1-(2-chlorophenyl)ethanol (209 mg, 1.33 mmol) usingcesium fluoride (580 mg, 3.82 mmol) in DMSO (10 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 398 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (d, J=6.3 Hz, 3H), 6.50-6.54 (m, 1H),7.30-7.34 (m, 2H), 7.43-7.47 (m, 2H), 8.25 (s, 1H), 8.38 (s, 5H).

Step 2: (S)-4-(3-(1-(2-chlorophenyl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(392 mg, 1.10 mmol) using iron powder (185 mg, 3.30 mmol) and ammoniumchloride (589 mg, 11.01 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield246 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz,3H), 5.57 (s, 2H), 6.44-6.48 (m, 1H), 6.64 (d, J=8.4 Hz, 2H), 7.28-7.32(m, 2H), 7.42-7.46 (m, 2H), 7.89-7.95 (m, 3H), 8.14 (s, 1H).

Intermediate 77 4-(3-(2-Chlorophenoxy)pyrazin-2-yl)aniline

Step 1: 2-(2-chlorophenoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (200 mg,0.85 mmol) with 2-chlorophenol (131 mg, 1.02 mmol) using cesiumcarbonate (415 mg, 1.27 mmol) in DMSO (5.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 151 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 7.34-7.40 (m, 1H), 7.45-7.52 (m, 2H), 7.63(d, J=7.2 Hz, 1H), 8.26 (s, 1H), 8.41 (s, 4H), 8.60 (s, 1H).

Step 2: 4-(3-(2-Chlorophenoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(151 mg, 0.46 mmol) using iron powder (129 mg, 2.30 mmol) and ammoniumchloride (247 mg, 4.61 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield89 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.62 (s, 2H), 6.66 (d,J=8.1 Hz, 2H), 7.29-7.33 (m, 1H), 7.39-7.43 (m, 2H), 7.61 (d, J=8.1 Hz,1H), 7.90-7.97 (m, 3H), 8.35 (s, 1H); APCI-MS (m/z) 298 (M+H)⁺.

Intermediate 78(R)-4-(3-(1-(2-Chloro-4-methylphenyl)ethoxy)pyrazin-2-yl)aniline

Step 1:(R)-2-(1-(2-Chloro-4-methylphenyl)ethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with (R)-1-(2-chloro-4-methylphenyl)ethanol (147 mg, 0.86mmol) using cesium fluoride (392 mg, 2.58 mmol) in DMSO (8.0 mL) as perthe procedure described in Step 1 of Intermediate 51 to yield 161 mg ofthe product; 1H NMR (300 MHz, DMSO-d₆) δ 1.64 (d, J=6.3 Hz, 3H), 2.26(s, 3H), 6.46-6.50 (m, 1H), 7.12-7.16 (m, 1H), 7.28-7.34 (m, 2H), 8.24(s, 1H), 8.37 (s, 5H); APCI-MS (m/z) 370 (M+H)⁺.

Step 2: (R)-4-(3-(1-(2-Chloro-4-methylphenyl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(188 mg, 0.51 mmol) using iron powder (85 mg, 1.52 mmol) and ammoniumchloride (272 mg, 5.08 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield140 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.61 (d, J=6.3 Hz,3H), 2.25 (s, 3H), 5.55 (s, 2H), 6.41-6.45 (m, 1H), 6.63 (d, J=6.9 Hz,2H), 7.12 (d, J=8.4 Hz, 1H), 7.26-7.34 (m, 2H), 7.87-7.91 (m, 3H), 8.13(s, 1H); APCI-MS (m/z) 340 (M+H)⁺.

Intermediate 794-(3-((3,5-Dimethylisoxazol-4-yl)methoxy)pyrazin-2-yl)aniline

Step 1:3,5-Dimethyl-4-(((3-(4-nitrophenyl)pyrazin-2-yl)oxy)methyl)isoxazole

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (112 mg,0.48 mmol) with (3,5-dimethylisoxazol-4-yl)methanol (61 mg, 0.48 mmol)using cesium fluoride (216 mg, 1.43 mmol) in DMSO (8.0 mL) as per theprocedure described in Step 1 of Intermediate 51 to yield 109 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 2.22 (s, 3H), 2.45 (s, 3H), 5.33(s, 2H), 8.22 (d, J=8.7 Hz, 2H), 8.32-8.38 (m, 3H), 8.43 (s, 1H).

Step 2: 4-(3-((3,5-Dimethylisoxazol-4-yl)methoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(102 mg, 0.31 mmol) using iron powder (52 mg, 0.94 mmol) and ammoniumchloride (167 mg, 3.13 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield56 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.23 (s, 3H), 2.43 (s,3H), 5.27 (s, 2H), 5.53 (s, 2H), 6.57 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.7Hz, 2H), 8.03 (s, 1H), 8.21 (s, 1H).

Intermediate 804-(3-(2-(3,5-Dimethylisoxazol-4-yl)ethoxy)pyrazin-2-yl)aniline

Step 1:3,5-Dimethyl-4-(2-((3-(4-nitrophenyl)pyrazin-2-yl)oxy)ethyl)isoxazole

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with 2-(3,5-dimethylisoxazol-4-yl)ethanol (121 mg, 0.86 mmol)using cesium fluoride (392 mg, 2.58 mmol) in DMSO (8.0 mL) as per theprocedure described in Step 1 of Intermediate 51 to yield 149 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 2.10 (s, 3H), 2.19 (s, 3H), 2.84(t, J=6.6 Hz, 2H), 4.51 (t, J=6.6 Hz, 2H), 8.18 (d, J=8.7 Hz, 2H),8.28-8.33 (m, 3H), 8.40 (s, 1H).

Step 2: 4-(3-(2-(3,5-Dimethylisoxazol-4-yl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(141 mg, 0.41 mmol) using iron powder (70 mg, 1.24 mmol) and ammoniumchloride (221 mg, 4.14 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield121 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (s, 3H), 2.24(s, 3H), 2.83 (t, J=6.6 Hz, 2H), 4.45 (t, J=6.6 Hz, 2H), 5.53 (s, 2H),6.58 (d, J=8.1 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.97 (s, 1H), 8.16 (s,1H); ESI-MS (m/z) 311 (M+H)⁺.

Intermediate 81 4-(3-((2-Chlorobenzyl)oxy)pyrazin-2-yl)aniline

Step 1: 2-((2-Chlorobenzyl)oxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with 2-chlorobenzylalcohol (123 mg, 0.86 mmol) using cesiumfluoride (392 mg, 2.58 mmol) in DMSO (8.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 110 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 5.59 (s, 2H), 7.38-7.42 (m, 2H), 7.49-7.53(m, 2H), 8.28-8.32 (m, 5H), 8.46 (s, 1H).

Step 2: 4-(3-((2-Chlorobenzyl)oxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(101 mg, 0.29 mmol) using iron powder (49 mg, 0.88 mmol) and ammoniumchloride (158 mg, 2.95 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield78 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 5.52 (s, 4H), 6.58 (d,J=7.8 Hz, 2H), 7.37-7.41 (m, 2H), 7.53-7.57 (m, 2H), 7.83 (d, J=8.4 Hz,2H), 8.02 (s, 1H), 8.22 (s, 1H); ESI-MS (m/z) 312 (M+H)⁺.

Intermediate 824-(3-(2-(4-Methylthiazol-5-yl)ethoxy)pyrazin-2-yl)aniline

Step 1: 5-(2-((3-Chloropyrazin-2-yl)oxy)ethyl)-4-methylthiazole

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(200 mg, 1.34 mmol) with 2-(4-methylthiazol-5-yl)ethanol (230 mg, 1.61mmol) using cesium fluoride (612 mg, 4.01 mmol) in DMSO (10 mL) as perthe procedure described in Step 1 of Intermediate 51 to yield 326 mg ofthe product; ¹H NMR (300 MHz, CDCl₃) δ 2.46 (s, 3H), 3.31 (t, J=6.3 Hz,2H), 4.55 (t, J=6.3 Hz, 2H), 7.93-8.01 (m, 2H), 8.63 (s, 1H).

Step 2: 4-Methyl-5-(2-((3-(4-nitrophenyl)pyrazin-2-yl)oxy)ethyl)thiazole

The titled compound was prepared by the reaction of Step 1 intermediate(160 mg, 0.63 mmol) with 4-nitrophenylboronic acid pinacol ester (187mg, 0.75 mmol) using potassium carbonate (259 mg, 1.88 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (26 mg, 0.03 mmol) in a mixture of DMSO andwater (12 mL, 3:1) at RT as per the procedure described in Step 1 ofIntermediate 1 to yield 96 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 2.27 (s, 3H), 3.32 (t, J=6.3 Hz, 2H), 4.61 (t, J=6.3 Hz, 2H), 8.16 (d,J=8.7 Hz, 2H), 8.26-8.33 (m, 3H), 8.41 (s, 1H), 8.83 (s, 1H); ESI-MS(m/z) 343 (M+H)⁺.

Step 3: 4-(3-(2-(4-Methylthiazol-5-yl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 2 intermediate(90 mg, 0.26 mmol) using iron powder (73 mg, 1.31 mmol) and ammoniumchloride (141 mg, 2.63 mmol) in a mixture of ethanol and water (18 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield56 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.31 (t,J=6.3 Hz, 2H), 4.54 (t, J=6.3 Hz, 2H), 5.53 (s, 2H), 6.56 (d, J=8.7 Hz,2H), 7.73 (d, J=9.0 Hz, 2H), 7.98 (s, 1H), 8.18 (s, 1H), 8.84 (s, 1H);ESI-MS (m/z) 313 (M+H)⁺.

Intermediate 83 4-(3-(Cyclohexylmethoxy)pyrazin-2-yl)aniline

Step 1: 2-(Cyclohexylmethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.86 mmol) with cyclohexylmethanol (99 mg, 0.86 mmol) using cesiumfluoride (392 mg, 2.58 mmol) in DMSO (8.0 mL) as per the proceduredescribed in Step 1 of Intermediate 51 to yield 141 mg of the product;¹H NMR (300 MHz, DMSO-d₆) δ 1.03-1.28 (m, 5H), 1.68-1.81 (m, 6H), 4.24(d, J=5.7 Hz, 2H), 8.25-8.32 (m, 2H), 8.33-8.41 (m, 4H).

Step 2: 4-(3-(Cyclohexylmethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(132 mg, 0.42 mmol) using iron powder (70 mg, 1.26 mmol) and ammoniumchloride (225 mg, 4.21 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield103 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.00-1.24 (m, 5H),1.68-1.81 (m, 5H), 3.15-3.21 (m, 1H), 4.16 (d, J=3.9 Hz, 2H), 5.51 (s,2H), 6.61 (d, J=8.7 Hz, 2H), 7.83 (d, J=7.2 Hz, 2H), 7.96 (s, 1H), 8.15(s, 1H); ESI-MS (m/z) 282 (M−H)⁻.

Intermediate 84 4-(3-(3-(Benzyloxy)azetidin-1-yl)pyrazin-2-yl)aniline

Step 1: 2-(3-(Benzyloxy)azetidin-1-yl)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (162 mg,0.69 mmol) with 3-(benzyloxy)azetidine hydrochloride (151 mg, 0.76 mmol)using cesium fluoride (418 mg, 2.75 mmol) in DMSO (8.0 mL) as per theprocedure described in Step 1 of Intermediate 51 to yield 217 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 3.52-3.59 (m, 2H), 3.84-3.92 (m,2H), 4.33-4.39 (m, 3H), 7.27-7.31 (m, 5H), 7.83 (d, J=8.1 Hz, 2H), 8.13(s, 1H), 8.21 (s, 1H), 8.31 (d, J=8.4 Hz, 2H); ESI-MS (m/z) 363 (M+H)⁺.

Step 2: 4-(3-(3-(Benzyloxy)azetidin-1-yl)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(209 mg, 0.57 mmol) using iron powder (97 mg, 1.72 mmol) and ammoniumchloride (308 mg, 5.76 mmol) in a mixture of ethanol and water (10 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield161 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 3.32-3.57 (m, 2H),3.86-3.91 (m, 2H), 4.34-4.37 (m, 1H), 4.38 (s, 2H), 5.40 (s, 2H), 6.61(d, J=8.4 Hz, 2H), 7.28-7.32 (m, 7H), 7.96 (s, 2H); ESI-MS (m/z) 333(M+H)⁺.

Intermediate 85 2-((3-(4-Aminophenyl)pyrazin-2-yl)amino)-2-phenylethanol

Step 1: 2-((3-Chloropyrazin-2-yl)amino)-2-phenylethanol

A mixture of 2,3-dichloropyrazine (1.0 g, 6.71 mmol) and(+)-2-amino-2-phenylethanol (1.02 g, 7.45 mmol) in 1,4-dioxane (15 mL)was refluxed overnight. The mixture was cooled to RT and concentratedunder vacuum. The residue obtained was diluted with ethyl acetate (30mL) and washed with water (30 mL) followed by brine (40 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography to yield 548 mg of the desired product; ¹H NMR (300 MHz,CDCl₃) δ 3.60-3.65 (m, 1H), 3.86-3.91 (m, 1H), 4.96-5.02 (m, 1H), 5.63(br s, 1H), 7.28-7.41 (m, 5H), 7.62 (s, 1H), 7.93 (s, 1H).

Step 2: 2-((3-(4-Aminophenyl)pyrazin-2-yl)amino)-2-phenylethanol

The titled compound was prepared by the reaction of Step 1 intermediate(200 mg, 0.80 mmol) with 4-aminophenylboronic acid pinacol ester (210mg, 0.96 mmol) using sodium carbonate (255 mg, 2.40 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II).dichloromethane complex (65 mg, 0.08 mmol) in a mixture of DMSO andwater (12 mL, 3:1) at 80° C. as per the procedure described in Step 1 ofIntermediate 1 to yield 127 mg of the product; ¹H NMR (300 MHz, DMSO-d₆)δ 3.34-3.42 (m, 1H), 3.56-3.62 (m, 1H), 4.80-4.84 (m, 1H), 5.43 (s, 2H),5.56-5.58 (m, 1H), 6.01 (br s, 1H), 6.62 (d, J=8.4 Hz, 2H), 7.29 (d,J=8.7 Hz, 2H), 7.32-7.36 (m, 5H), 7.75 (s, 1H), 7.86 (s, 1H).

Intermediate 86(R)-4-(3-(1-(2,4-Dimethylphenyl)ethoxy)pyrazin-2-yl)aniline

Step 1: (R)-2-(1-(2,4-Dimethylphenyl)ethoxy)-3-(4-nitrophenyl)pyrazine

The titled compound was prepared by the reaction of2-chloro-3-(4-nitrophenyl)pyrazine (Step 1 of intermediate 11) (203 mg,0.85 mmol) with (R)-1-(2,4-dimethylphenyl)ethanol (128 mg, 0.85 mmol)using cesium fluoride (386 mg, 2.54 mmol) in DMSO (8.0 mL) as per theprocedure described in Step 1 of Intermediate 51 to yield 123 mg of theproduct; ¹H NMR (300 MHz, DMSO-d₆) δ 1.60 (d, J=6.3 Hz, 3H), 2.19 (s,3H), 2.35 (s, 3H), 6.35-6.42 (m, 1H), 6.91-6.96 (m, 2H), 7.23 (d, J=7.8Hz, 1H), 8.22 (s, 1H), 8.29-8.36 (m, 5H); APCI-MS (m/z) 350 (M+H)⁺.

Step 2: (R)-4-(3-(1-(2,4-Dimethylphenyl)ethoxy)pyrazin-2-yl)aniline

The titled compound was prepared by the reduction of Step 1 intermediate(117 mg, 0.33 mmol) using iron powder (56 mg, 1.00 mmol) and ammoniumchloride (180 mg, 3.34 mmol) in a mixture of ethanol and water (12 mL,5:1) as per the procedure described in Step 4 of Intermediate 9 to yield72 mg of the product; ¹H NMR (300 MHz, DMSO-d₆) δ 1.58 (d, J=6.3 Hz,3H), 2.20 (s, 3H), 2.35 (s, 3H), 5.52 (s, 2H), 6.33-6.37 (m, 1H), 6.63(d, J=8.1 Hz, 2H), 6.93-6.99 (m, 2H), 7.21-7.27 (m, 2H), 7.90 (s, 1H),7.92 (s, 1H), 8.10 (s, 1H).

Intermediate 87 4-(3-(4-(Oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)aniline

Step 1: tert-Butyl 4-(3-Chloropyrazin-2-yl)piperazine-1-carboxylate

The titled compound was prepared by the reaction of 2,3-dichloropyrazine(500 mg, 3.35 mmol) with tert-butyl piperazine-1-carboxylate (625 mg,3.35 mmol) in dimethylacetamide (10 mL) as per the procedure describedin Step 1 of Intermediate 7 to yield 882 mg of the product; ¹H NMR (300MHz, CDCl₃) δ 1.48 (s, 9H), 3.39-3.45 (m, 4H), 3.57-3.60 (m, 4H), 7.91(s, 1H), 8.11 (s, 1H).

Step 2: 2-Chloro-3-(piperazin-1-yl)pyrazine

To a stirred solution of Step 1 intermediate (870 mg, 2.92 mmol) indichloromethane (10 mL) was added trifluoroacetic acid (4.0 mL) at 0° C.and the mixture was stirred for 6 h at RT. The reaction mixture wasbasified (pH 10) with 50% aqueous solution of sodium hydroxide and theaqueous mixture was extracted with dichloromethane (2×100 mL). Thecombined organic layers were washed with water (100 mL) and brine (50mL). The solvent was removed under vacuum to obtain 378 mg of the titledproduct; APCI-MS (m/z) 199 (M+H)+.

Step 3: 2-Chloro-3-(4-(oxetan-3-yl)piperazin-1-yl)pyrazine

A mixture of Step 2 intermediate (378 mg, 1.90 mmol), 3-oxetanone (205mg, 2.85 mmol) and catalytic amount of acetic acid in 1,2-dichloroethane(10 mL) was stirred for 2 h at RT. Sodium triacetoxyborohydride (806 mg,3.85 mmol) was added to the reaction mixture and allowed to stirovernight at RT. The reaction mixture was diluted with ethyl acetate(100 mL) and washed with saturated aqueous sodium bicarbonate solution(2×30 mL) followed by brine (50 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography toyield 273 mg of the titled product; ¹H NMR (300 MHz, CDCl₃) δ 2.52-2.56(m, 4H), 3.52-3.62 (m, 5H), 4.65-3.73 (m, 3H), 7.89 (s, 1H), 8.11 (s,2H); APCI-MS (m/z) 255 (M+H)⁺.

Step 4: 4-(3-(4-(Oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)aniline

The titled compound was prepared by the reaction of Step 3 intermediate(255 mg, 1.00 mmol) with 4-aminophenylboronic acid pinacol ester (263mg, 1.20 mmol) using potassium carbonate (415 mg, 3.00 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (82 mg,0.10 mmol) in a mixture of DMSO and water (12 mL, 3:1) at 80° C. as perthe procedure described in Step 1 of Intermediate 1 to yield 123 mg ofthe product; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28-2.32 (m, 3H), 3.08-3.12(m, 4H), 3.37-3.46 (m, 2H), 4.41 (t, J=5.7 Hz, 2H), 4.52 (t, J=6.3 Hz,2H), 5.42 (br s, 2H), 6.60 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H),8.01 (s, 1H), 8.09 (s, 1H); ESI-MS (m/z) 312 (M+H)⁺.

EXAMPLES

The examples were prepared by following the methods described below:

Method A Preparation ofN-(4-(3-(4-chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide (Example 1)

To a stirred solution of Intermediate 1 (92 mg, 0.32 mmol) andIntermediate 2 (70 mg, 0.32 mmol) in DMF (5.0 mL) at 0° C. was addedN,N′-diisopropylethylamine (160 μL, 0.97 mmol) followed bypropylphosphonic anhydride (50% in EtOAc, 194 μL, 0.65 mmol). Themixture was stirred overnight at RT. The reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (75 mL×2). Thecombined organic layer was washed with brine (100 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude material obtained was purified by silica gel column chromatographyto obtain 53 mg of the product; H NMR (300 MHz, DMSO-d₆) δ 0.88 (t,J=7.2 Hz, 3H), 2.15-2.26 (m, 2H), 3.69 (s, 2H), 7.29-7.45 (m, 10H), 7.56(d, J=8.7 Hz, 2H), 8.66 (d, J=8.7 Hz, 2H), 10.32 (s, 1H); APCI-MS (m/z)477 (M+H)⁺.

Method B Preparation ofN-(4-(3-(4-chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide (Example 2)

Step 1:N-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-oxopropyl)phenyl)acetamide

The titled compound was prepared by the reaction of Intermediate 1 (133mg, 0.47 mmol) and Intermediate 3 (120 mg, 0.52 mmol) usingN,N′-diisopropylethylamine (269 μL, 1.57 mmol) and propylphosphonicanhydride (50% in EtOAc, 624 μL, 1.05 mmol) in DMF (5.0 mL) at RT as perthe procedure described in Method A to give 143 mg of the product;APCI-MS (m/z) 492 (M+H)⁺.

Step 2:N-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide

To a stirred solution of step 1 intermediate (134 mg, 0.27 mmol) inmethanol (5.0 mL) at 0° C. was added sodium borohydride (125 mg, 0.32mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixturewas quenched with aq. ammonium chloride (20 mL), poured into water (20mL) and extracted with ethyl acetate (70 mL×2). The combined organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material obtained was purified by silica gelcolumn chromatography to obtain 64 mg of the product; ¹H NMR (300 MHz,DMSO-d₆) δ 1.07 (d, J=5.7 Hz, 3H), 3.70 (s, 2H), 3.99-4.06 (m, 1H), 5.51(d, J=6.0 Hz, 1H), 7.34 (d, J=8.1 Hz, 3H), 7.39-7.45 (m, 7H), 7.56 (d,J=8.1 Hz, 2H), 8.67 (d, J=3.9 Hz, 2H), 10.34 (s, 1H); ESI-MS (m/z) 494(M+H)⁺.

Method C Preparation of(S)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide(Example 52)

Step 1:2-(4-(1,1-Difluoro-2-oxopropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide

The titled compound was prepared by the reaction of Intermediate 39 (60mg, 0.22 mmol) and Intermediate 3 (50 mg, 0.22 mmol) usingN,N′-diisopropylethylamine (113 μL, 0.66 mmol) and propylphosphonicanhydride (50% in EtOAc, 263 μL, 0.44 mmol) in DMF (6.0 mL) as per theprocedure described in Method A to yield 103 mg of the product; ¹H NMR(300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2 Hz, 3H), 2.26 (q, J=7.2 Hz, 2H),2.35 (s, 3H), 3.70 (s, 2H), 7.16-7.30 (m, 5H), 7.43-7.52 (m, 5H), 7.95(s, 2H), 8.66 (s, 1H), 8.72 (s, 1H), 10.29 (s, 1H).

Step 2:(S)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide(Crude)

To a stirred solution of (R)-(+)-2-methyl-CBS-oxaborolidine (1M intoluene, 0.41 mL) [Ref: (i) Corey, E. J; Helal, C. J. Angew. Chem. Int.Ed. 1998, 37, 1986-2012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S. JAm. Chem. Soc. 1987, 109 (18), 5551-5553] in anhydrous THF (10 mL) wasadded borane dimethyl sulfide complex (86 μL, 0.91 mmol) at 0° C. andthe mixture was stirred for 20 min at the same temperature. A solutionof Step 1 Intermediate (400 mg, 0.82 mmol) in THF (10 mL) was drop wiseadded to the reaction mixture over a period of 10 min at 0° C. Theresultant mixture was stirred at RT for 30 min. The reaction mixture wasquenched with methanol (10 mL) and concentrated under reduced pressure.The residue obtained was purified by flash silica gel columnchromatography to yield 371 mg of the titled product; ¹H NMR (300 MHz,DMSO-d₆) δ 0.85 (t, J=7.2 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 2.26 (q,J=7.2 Hz, 2H), 3.67 (s, 2H), 4.01-4.05 (m, 1H), 5.50 (d, J=6.0 Hz, 1H),7.14-7.34 (m, 6H), 7.36-7.49 (m, 6H), 8.67 (s, 1H), 8.73 (s, 1H), 10.28(s, 1H); APCI-MS (m/z) 488 (M+H)+; chiral HPLC purity: 84.85%.

Step 3:(S)-(S)-1-(4-(2-((4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)amino)-2-oxoethyl)phenyl)-1,1-difluoropropan-2-yl2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoate

To a stirred solution of Step 2 product (300 mg, 0.62 mmol),N-benzyloxycarbonyl-L-phenylalanine (239 mg, 0.80 mmol) and DIPEA (0.3mL, 1.84 mmol) in dichloromethane (10 mL) were added BOP (354 mg, 0.80mmol) and DMAP (38 mg, 0.31 mmol) at 0° C. The resultant mixture waswarmed up to RT and stirred for 16 h. The reaction mixture was dilutedwith ethyl acetate (200 mL) and washed with saturated aqueous solutionof ammonium chloride (100 mL), saturated aqueous sodium bicarbonatesolution (100 mL), water (100 mL) and brine (100 mL). The organic layerwas dried over anhydrous sodium sulfate, concentrated and the residuethus obtained was purified by flash silica gel column chromatography toyield 738 mg of the titled product; APCI-MS (m/z) 769 (M+H)⁺.

Step 4:(S)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide

To a stirred solution of Step 3 Intermediate (96 mg, 0.13 mmol) in amixture of THF (3.0 mL), methanol (1.0 mL) and water (1.0 mL) was addedlithium hydroxide monohydrate (16 mg, 0.38 mmol) and the mixture wasstirred at RT for 30 min. The reaction mixture was quenched withsaturated aqueous solution of ammonium chloride (10 mL) and the productwas extracted in ethyl acetate (2×20 mL). The combined organic layerswere washed with water (20 mL) and brine (10 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue obtained was purified by flash silica gel columnchromatography to yield 38 mg of the titled product; ¹H NMR (300 MHz,DMSO-d₆) δ 0.85 (t, J=7.2 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 2.26 (q,J=7.2 Hz, 2H), 3.67 (s, 2H), 4.02-4.05 (m, 1H), 5.49 (d, J=6.0 Hz, 1H),7.16-7.34 (m, 6H), 7.39-7.49 (m, 6H), 8.66 (s, 1H), 8.72 (s, 1H), 10.27(s, 1H); APCI-MS (m/z) 488 (M+H)+; Chiral HPLC purity: 97.34%.

Preparation of(R)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide (Example 53)

Step 1:2-(4-(1,1-Difluoro-2-oxopropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide

The titled compound was prepared by the reaction of Intermediate 39 (60mg, 0.22 mmol) and Intermediate 3 (50 mg, 0.22 mmol) usingN,N′-diisopropylethylamine (113 μL, 0.66 mmol) and propylphosphonicanhydride (50% in EtOAc, 263 μL, 0.44 mmol) in DMF (6.0 mL) as per theprocedure described in Method A to yield 103 mg of the product as solid;¹H NMR (300 MHz, DMSO-d₆) δ δ 0.85 (t, J=7.2 Hz, 3H), 2.26 (q, J=7.2 Hz,2H), 2.35 (s, 3H), 3.70 (s, 2H), 7.16-7.30 (m, 5H), 7.43-7.52 (m, 5H),7.95 (s, 2H), 8.66 (s, 1H), 8.72 (s, 1H), 10.29 (s, 1H).

Step 2:(R)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide(Crude)

To a stirred solution of (S)-(+)-2-methyl-CBS-oxaborolidine (1M intoluene, 0.36 mL) [Ref: (i) Corey, E. J; Helal, C. J. Angew. Chem. Int.Ed. 1998, 37, 1986-2012 (ii) Corey, E. J.; Bakshi, R. K.; Shibata, S. JAm. Chem. Soc. 1987, 109 (18), 5551-5553] in anhydrous THF (10 mL) wasadded borane dimethyl sulfide complex (75 μL, 0.79 mmol) at 0° C. andthe mixture was stirred for 20 min at the same temperature. A solutionof Step 1 Intermediate (350 mg, 0.72 mmol) in THF (5.0 mL) was drop wiseadded to the reaction mixture over a period of 10 min at 0° C. Theresultant mixture was stirred at RT for 30 min. The reaction mixture wasquenched with methanol (10 mL) and concentrated under reduced pressure.The residue obtained was purified by flash silica gel columnchromatography to yield 338 mg of the titled product; ¹H NMR (300 MHz,DMSO-d₆) δ 0.85 (t, J=7.2 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 2.26 (q,J=7.2 Hz, 2H), 3.67 (s, 2H), 4.01-4.05 (m, 1H), 5.50 (d, J=6.0 Hz, 1H),7.14-7.34 (m, 6H), 7.36-7.49 (m, 6H), 8.67 (s, 1H), 8.73 (s, 1H), 10.28(s, 1H); APCI-MS (m/z) 488 (M+H)+; chiral HPLC purity: 84.85%.

Step 3:(S)-(R)-1-(4-(2-((4-(3-(2-Ethylphenyl)pyrazin-2-yl)phenyl)amino)-2-oxoethyl)phenyl)-1,1-difluoropropan-2-yl2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoate

To a stirred solution of Step 2 product (150 mg, 0.30 mmol),N-benzyloxycarbonyl-L-phenylalanine (120 mg, 0.40 mmol) and DIPEA (0.16mL, 0.92 mmol) in dichloromethane (15 mL) were added BOP (177 mg, 0.40mmol) and DMAP (19 mg, 0.15 mmol) at 0° C. The resultant mixture waswarmed up to RT and stirred for 16 h. The reaction mixture was dilutedwith ethyl acetate (50 mL) and washed with saturated aqueous solution ofammonium chloride (50 mL), saturated aqueous sodium bicarbonate solution(50 mL), water (50 mL) and brine (50 mL). The organic layer was driedover anhydrous sodium sulfate, concentrated and the residue thusobtained was purified by flash silica gel column chromatography to yield108 mg of the titled product; APCI-MS (m/z) 769 (M+H)⁺.

Step 4:(R)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide

To a stirred solution of Step 3 Intermediate (105 mg, 0.14 mmol) in amixture of THF (3.0 mL), methanol (1.0 mL) and water (1.0 mL) was addedlithium hydroxide monohydrate (17 mg, 0.40 mmol) and the mixture wasstirred at RT for 30 min. The reaction mixture was quenched withsaturated aqueous solution of ammonium chloride (10 mL) and the productwas extracted in ethyl acetate (2×20 mL). The combined organic layerswere washed with water (20 mL) and brine (10 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue obtained was purified by flash silica gel columnchromatography to yield 48 mg of the titled product as solid; ¹H NMR(300 MHz, DMSO-d₆) δ 0.84 (t, J=7.8 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H),2.26 (q, J=7.8 Hz, 2H), 3.67 (s, 2H), 4.01-4.05 (m, 1H), 5.50 (d, J=6.0Hz, 1H), 7.14-7.34 (m, 6H), 7.40-7.49 (m, 6H), 8.66 (s, 1H), 8.73 (s,1H), 10.28 (s, 1H); APCI-MS (m/z) 488 (M+H)+; Chiral HPLC purity:95.86%.

Chemical name, structure Intermediate No., method of preparation andanalytical data of Example 3-51 & 54-99 are given below in Table 1.

TABLE 1 Chemical name, structure Intermediate No., method of preparationand analytical data of Example 3-51 & 54-99 Chemical Name Example andIntermediate/ No. Structure Method Analytical Data Example 3 

Intermediate 1 and Intermediate 10 Method A ¹H NMR (300 MHz, DMSO- d₆) δ3.35 (s, 3H), 3.71 (s, 2H), 3.88 (t, J = 13.8 Hz, 2H), 7.34 (d, J = 8.1Hz, 2H), 7.39-7.52 (m, 7H), 7.56 (d, J = 8.1 Hz, 3H), 8.67 (d, J = 3.9Hz, 2H), 10.35 (s, 1H); APCI-MS (m/z) 494 (M + H)⁺. N-(4-(3-(4-Chlorophenyl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-methoxyethyl)phenyl)acetamide Example 4 

Intermediate 3 and Intermediate 4 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.3 Hz, 3H), 3.70 (s, 2H), 3.99-4.05 (m, 1H), 5.49 (d, J =6.0 Hz, 1H), 7.21-7.43 (m, 8H), 7.42-7.57 (m, 4H), 8.68 (d, J = 8.1 Hz,2H), 10.33 (s, 1H). APCI-MS (m/z) 494 (M + H)⁺. N-(4-(3-(3-Chlorophenyl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 5 

Intermediate 2 and Intermediate 11 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.87 (t, J = 7.2 Hz, 3H), 2.13-2.20 (m, 2H), 3.66 (s, 2H), 7.26 (d, J =8.7 Hz, 2H), 7.40-7.51 (m, 10H), 8.67 (s, 1H), 8.75 (s, 1H), 10.27 (s,1H); ESI-MS (m/z) 479 (M + H)⁺. N-(4-(3-(2- Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 6 

Intermediate 2 and Intermediate 12 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.15-2.22 (m, 2H), 3.70 (s, 2H), 7.30-7.45 (m,8H), 7.52-7.64 (m, 3H), 8.71 (s, 1H), 8.76 (s, 1H), 10.33 (s, 1H);APCI-MS (m/z) 497 (M + H)⁺. N-(4-(3-(4-Chloro-2- fluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 7 

Intermediate 2 and Intermediate 14 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.87 (t, J = 6.9 Hz, 3H), 2.12-2.19 (m, 2H), 3.67 (s, 2H), 7.14-7.20 (m,4H), 7.33-7.45 (m, 9H), 7.74-7.77 (m, 1H), 8.63 (br s, 1H), 10.25 (s,1H); APCI-MS (m/z) 477 (M + H)⁺. N-(4-(3-(4- Chlorophenyl)pyridin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 8 

Intermediate 3 and Intermediate 5 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.05 (d, J = 6.3 Hz, 3H), 3.68 (s, 2H), 3.99-4.04 (m, 1H), 5.48 (d, J =6.3 Hz, 1H), 7.15 (t, J = 8.7 Hz, 2H), 7.29-7.42 (m, 7H), 7.54 (d, J =8.4 Hz, 2H), 8.64 (d, J = 3.3 Hz, 2H), 10.31 (s, 1H); APCI-MS (m/z) 478(M + H)⁺. 2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(4-fluorophenyl)pyrazin-2- yl)phenyl)acetamide Example 9 

Intermediate 3 and Intermediate 6 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.05 (d, J = 6.3 Hz, 3H), 3.68 (s, 2H), 3.99-4.05 (m, 1H), 5.49 (d, J =6.0 Hz, 1H), 7.14-7.17 (m, 2H), 7.32-7.42 (m, 7H), 7.56 (d, J = 8.7 Hz,2H), 8.66 (s, 1H), 8.69 (s, 1H), 10.33 (s, 1H); APCI-MS (m/z) 496 (M +H)⁺. 2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(3,4-difluorophenyl)pyrazin-2- yl)phenyl)acetamide Example 10

Intermediate 2 and Intermediate 13 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.87 (t, J = 7.5 Hz, 3H), 2.09-2.20 (m, 2H), 3.68 (s, 2H), 7.13-7.22 (m,2H), 7.30 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 3.3 Hz, 4H), 7.53 (d, J =8.1 Hz, 2H), 7.61-7.65 (m, 1H), 8.69 (s, 1H), 8.73 (s, 1H), 10.31 (s,1H); ESI-MS (m/z) 480 (M + H)⁺. N-(4-(3-(2,4- Difluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 11

Intermediate 2 and Intermediate 15 Method A ¹H NMR (300 MHz, DMSO- d₆) δ1.89 (t, J = 7.8 Hz, 3H), 2.11-2.27 (m, 2H), 3.69 (s, 2H), 7.11 (t, J =8.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 3H), 7.43-7.59 (m, 8H), 8.71 (s, 1H),8.74 (s, 1H), 10.31 (s, 1H); ESI-MS (m/z) 462 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (2-fluorophenyl)pyrazin-2-yl)phenyl)acetamide Example 12

Intermediate 2 and Intermediate 16 Method A ¹H NMR (300 MHz, DMSO- d₆) δ1.89 (t, J = 7.2 Hz, 3H), 2.14-2.19 (m, 2H), 3.70 (s, 2H), 7.34 (d, J =8.4 Hz, 2H), 7.49 (br s, 4H), 7.54- 7.64 (m, 4H), 7.72 (d, J = 8.1 Hz,2H), 8.73 (d, J = 6.0 Hz, 2H), 10.34 (s, 1H); ESI-MS (m/z) 512 (M + H)⁺.2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3- (4-(trifluoromethyl)phenyl)pyrazin- 2-yl)phenyl)acetamide Example 13

Intermediate 2 and Intermediate 17 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.5 Hz, 3H), 2.16-2.23 (m, 2H), 2.29 (s, 3H), 3.70 (s, 2H),7.13 (d, J = 7.8 Hz, 2H), 7.26-7.35 (m, 4H), 7.45 (d, J = 3.6 Hz, 4H),7.54 (d, J = 8.4 Hz, 2H), 8.63 (s, 2H), 10.32 (s, 1H). 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (p-tolyl)pyrazin-2- yl)phenyl)acetamideExample 14

Intermediate 2 and Intermediate 18 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.2 Hz, 3H), 2.10-2.15 (m, 2H), 3.74 (s, 2H), 6.99 (t, J =9.0 Hz, 2H), 7.09-7.12 (m, 2H), 7.27 (d, J = 8.7 Hz, 3H), 7.38 (d, J =9.3 Hz, 5H), 7.47 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 7.8 Hz, 1H), 8.67(s, 1H); APCI-MS (m/z) 461 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (4-fluorophenyl)pyridin-2-yl)phenyl)acetamide Example 15

Intermediate 2 and Intermediate 19 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.15- 2.22 (m, 2H), 3.70 (s, 2H), 7.33-7.57(m, 13H), 8.67 (s, 2H), 10.32 (s, 1H); ESI-MS (m/z) 444 (M + H)⁺.2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3- phenylpyrazin-2-yl)phenyl)acetamide Example 16

Intermediate 2 and Intermediate 20 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 2.16-2.23 (m, 2H), 3.71 (s, 2H), 7.33 (d, J =8.4 Hz, 2H), 7.45 (s, 4H), 7.57 (d, J = 8.1 Hz, 4H), 7.82 (d, J = 7.8Hz, 2H), 8.72 (d, J = 6.6 Hz, 2H), 10.35 (s, 1H); ESI-MS (m/z) 469 (M +H)⁺. N-(4-(3-(4- Cyanophenyl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 17

Intermediate 2 and Intermediate 21 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 5.7 Hz, 3H), 2.18-2.22 (m, 2H), 3.36 (br s, 2H), 7.32-7.47(m, 8H), 7.56 (d, J = 8.1 Hz, 2H), 8.55 (s, 2H), 8.74 (d, J = 9.6 Hz,2H), 10.36 (s, 1H); ESI-MS (m/z) 445 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (pyridin-4-yl)pyrazin-2-yl)phenyl)acetamide Example 18

Intermediate 3 and Intermediate 7 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.05 (d, J = 7.5 Hz, 3H), 1.94-2.07 (m, 4H), 3.19 (s, 4H), 3.71 (s, 2H),4.02 (m, 1H), 5.49 (d, J = 6 Hz, 1H), 7.43 (s, 4H), 7.70 (d, J = 7.8 Hz,2H), 7.87 (d, J = 7.8 Hz, 2H), 8.12 (s, 1H), 8.18 (s, 1H), 10.37 (br s,1H); ESI-MS (m/z) 503 (M + H)⁺. 2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3- (4,4-difluoropiperidin-1- yl)pyrazin-2-yl)phenyl)acetamide Example 19

Intermediate 3 and Intermediate 8 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.08 (d, J = 6.9 Hz, 3H), 3.06 (br s, 4H), 3.61 (br s, 4H), 3.73 (s,2H), 4.00- 4.07 (m, 1H), 5.51 (d, J = 5.1 Hz, 1H), 7.44 (s, 4H), 7.72(d, J = 8.7 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 8.14 (s, 1H), 8.18 (s,1H), 10.38 (s, 1H) APCI-MS (m/z) 469 (M + H)⁺. 2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3- morpholinopyrazin-2- yl)phenyl)acetamideExample 20

Intermediate 2 and Intermediate 22 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.5 Hz, 3H), 2.25 (s, 5H), 3.70 (s, 2H), 6.42 (s, 1H),7.14-7.22 (m, 6H), 7.45 (s, 4H), 7.60 (d, J = 7.2 Hz, 1H), 10.36 (s,1H); ESI-MS (m/z) 464 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(5- (4-fluorophenyl)-3-methyl-1H-pyrazol-1-yl)phenyl)acetamide Example 21

Intermediate 2 and Intermediate 9 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.88 (t, J = 7.5 Hz, 3H), 1.38 (s, 9H), 2.14-2.20 (m, 2H), 3.64 (s, 2H),6.94 (d, J = 8.1 Hz, 2H), 7.27-7.44 (m, 10H), 7.70 (s, 1H), 10.11 (s,1H); ESI-MS (m/z) 505 (M + H)⁺. N-(4-(1-(tert-Butyl)-5-(4-fluorophenyl)-1H-pyrazol-4- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 22

Intermediate 3 and Intermediate 9 Method B '¹H NMR (300 MHz, DMSO- d₆) δ1.05 (d, J = 7.5 Hz, 3H), 1.38 (s, 9H), 3.63 (s, 2H),4.01 (m, 1H), 5.49(d, J = 6.0 Hz, 1H), 6.94 (d, J = 8.1 Hz, 2H), 7.24-7.41 (m, 10H), 7.70(s, 1H), 10.11 (s, 1H); ESI-MS (m/z) 522 (M + H)⁺.N-(4-(1-(tert-Butyl)-5-(4- fluorophenyl)-1H-pyrazol-4-yl)phenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example23

Intermediate 2 and Intermediate 23 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 5.7 Hz, 3H), 2.18-2.23 (m, 2H), 3.77 (s, 5H), 7.11 (s, 1H),7.44-7.48 (m, 6H), 7.68-7.75 (m, 3H), 8.48 (s, 1H), 8.55 (s, 1H), 10.41(s, 1H); ESI-MS (m/z) 448 (M + H)⁺. 2-(4-1,1-Difluoropropyl)phenyl)-N-(4-(3- (1-methyl-1H-pyrazol-4- yl)pyrazin-2-yl)phenyl)acetamide Example 24

Intermediate 2 and Intermediate 24 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.5 Hz, 3H), 2.07 (s, 3H), 2.15 (q, J = 9.3 Hz, 2H),3.10-3.19 (m, 4H), 3.44 (br s, 2H), 3.57 (br s, 2H), 3.78 (s, 2H), 7.26(s, 1H), 7.40-7.57 (m, 6H), 7.87 (d, J = 8.4 Hz, 2H), 8.07 (s, 1H), 8.17(s, 1H); ESI-MS (m/z) 494 (M + H)⁺. N-(4-(3-(4-Acetylpiperazin-1-yl)pyrazin-2-yl)phenyl)-2-(4- (1,1- difluoropropyl)phenyl)acetamideExample 25

Intermediate 2 and Intermediate 25 Method A ¹H NMR (300 MHz, CDCl₃) δ0.98 (t, J = 7.2 Hz, 3H), 2.10-2.20 (m, 2H), 3.56 (s, 3H), 3.77 (s, 2H),6.36 (d, J = 9.3 Hz, 1H), 7.15 (d, J = 9.3 Hz, 1H), 7.26-7.53 (m, 7H),7.66 (s, 1H), 7.80 (s, 1H), 8.49 (s, 1H), 8.53 (s, 1H); APCI-MS (m/z)475 (M + H)⁺. 2-(4-(1,1- Difiuoropropyl)phenyl)-N-(4-(3-(1-methyl-6-oxo-1,6- dihydropyridin-3-yl)pyrazin-2- yl)phenyl)acetamideExample 26

Intermediate 2 and Intermediate 26 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.2 Hz, 3H), 2.10-2.17 (m, 2H), 3.80 (s, 2H), 7.20-7.40 (m,9H), 7.49 (s, 2H), 8.29-8.31 (m, 1H), 8.59 (s, 2H); APCI-MS (m/z) 496(M + H)⁺. N-(4-(3-(4- Chlorophenyl)pyrazin-2-yl)-2-fluorophenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 27

Intermediate 2 and Intermediate 27 Method A ¹H NMR (300 MHz, CDCl₃) δ0.90 (t, J = 7.2 Hz, 3H), 2.15-2.23 (m, 2H), 3.70-3.76 (m, 5H), 6.89 (d,J = 7.2 Hz, 2H), 7.35 (d, J = 7.8 Hz, 4H), 7.46 (s, 4H), 7.56 (d, J =7.8 Hz, 2H), 8.61 (s, 2H), 10.33 (s, 1H); APCI-MS (m/z) 474 (M + H)⁺.2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3- (4-methoxyphenyl)pyrazin-2-yl)phenyl)acetamide Example 28

Intermediate 2 and Intermediate 28 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 2.17-2.22 (m, 2H), 3.72 (s, 2H), 7.18-7.31 (m,7H), 7.46 (br s, 4H), 6.67 (d, J = 7.8 Hz, 2H), 10.45 (s, 1H).2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(5- (4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)acetamide Example 29

Intermediate 2 and Intermediate 29 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.98 (t, J = 7.2 Hz, 3H), 2.10-2.20 (m, 2H), 3.69 (s, 2H), 7.14 (s, 1H),7.20 (d, J = 8.4 Hz, 2H), 7.42-7.60 (m, 10H), 10.38 (s, 1H).N-(4-(5-(2-Chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 30

Intermediate 2 and Intermediate 30 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.2 Hz, 3H), 2.08-2.22 (m, 2H), 3.72 (s, 2H), 7.12-7.38 (m,12H), 7.47 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.5Hz, 1H), 8.71 (s, 1H);APCI-MS (m/z) 477 (M + H)⁺. N-(4-(3-(2- Chlorophenyl)pyridin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 31

Intermediate 2 and Intermediate 31 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 1.90 (s, 3H), 2.15-2.24 (m, 2H), 3.68 (s, 2H),7.20-7.29 (m, 6H), 7.42-7.49 (m, 6H), 8.67 (s, 1H), 8.72 (s, 1H), 10.28(s, 1H); APCI-MS (m/z) 458 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (o-tolyl)pyrazin-2-2-yl)phenyl)acetamide Example 32

Intermediate 2 and Intermediate 32 Method A ¹H NMR (300 MHz, CDCl₃) δ0.98 (t, J = 7.2 Hz, 3H), 2.06-2.22 (m, 2H), 2.50 (s, 3H), 2.72 (s, 4H),3.39 (s, 4H), 3.79 (s, 2H), 7.42-7.48 (m, 3H), 7.59 (d, J = 8.1 Hz, 2H),7.73 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 8.05 (d, J = 1.8 Hz, 1H), 8.16(d, J = 2.1 Hz, 1H); APCI-MS (m/z) 466 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (4-methylpiperazin-1-yl)pyrazin-2-yl)phenyl)acetamide Example 33

Intermediate 2 and Intermediate 33 Method A ¹H NMR (300 MHz, CDCl₃) δ0.98 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 6.9 Hz, 3H), 2.07-2.20 (m, 2H),2.62-2.73 (m, 6H), 3.40 (s, 4H), 3.79 (s, 2H), 7.43-7.47 (m, 3H), 7.58(d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.05 (s,1H), 8.15 (s, 1H); APCI-MS (m/z) 480 (M + H)⁺. 2-(4-(1,1-Difiuoropropyl)phenyl)-N-(4-(3- (4-ethylpiperazin-1-yl)pyrazin-2-yl)phenyl)acetamide Example 34

Intermediate 2 and Intermediate 34 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 2.11-2.27 (m, 2H), 3.70 (s, 2H), 7.11 (d, J =8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H),7.44-7.49 (m, 5H), 7.55 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H),8.64 (d, J = 4.2 Hz, 1H), 10.28 (s, 1H); APCI-MS (m/z) 477 (M + H)⁺.N-(4-(2-(4- Chlorophenyl)pyridin-3- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 35

Intermediate 2 and Intermediate 35 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 6.9 Hz, 3H), 2.17-2.23 (m, 2H), 3.69 (s, 2H), 7.09 (d, J =7.8 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.36-7.46 (m, 7H), 7.55 (d, J =8.4 Hz, 2H), 8.57 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 10.27 (s, 1H);APCI- MS (m/z) 477 (M + H)⁺. N-(4-(4-(4- Chlorophenyl)pyridin-3-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 36

Intermediate 2 and Intermediate 36 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.3 Hz, 6H), 2.07-2.22 (m, 2H),2.45 (t, J = 11.1 Hz, 2H), 3.42 (d, J = 12.3 Hz, 2H), 2.62-2.72 (m, 2H),3.78 (s, 2H), 7.31 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.47-7.57 (m, 4H),7.86 (d, J = 8.4 Hz, 2H), 8.07 (s, 1H), 8.11 (s, 1H); APCI-MS 2-(4-(1,1-(m/z) 481 (M + H)⁺. Difluoropropyl)phenyl)-N-(4-(3- ((2S,6R)-2,6-dimethylmorpholino)pyrazin-2- yl)phenyl)acetamide Example 37

Intermediate 3 and Intermediate 11 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.06 (d, J = 6.3 Hz, 3H), 3.68 (s, 2H), 4.01-4.05 (m, 1H), 5.49 (d, J =6.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.39-7.45 (m, 8H), 7.49 (d, J =7.8 Hz, 2H), 8.69 (s, 1H), 8.77 (s, 1H), 10.29 (s, 1H); ESI-MS (m/z) 494(M + H)⁺. N-(4-(3-(2- Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example38

Intermediate 2 and Intermediate 37 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.15-2.22 (m, 2H), 2.28 (s, 3H), 3.68 (s, 2H),6.39 (s, 1H), 7.08 (d, J = 9.0 Hz, 2H), 7.44-7.53 (m, 8H), 7.66 (s, 1H),10.30 (s, 1H); ESI- MS (m/z) 514 (M)⁺. N-(4-(5-(2,4-Dichlorophenyl)-3-methyl-1H-pyrazol-1-yl)phenyl)- 2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 39

Intermediate 2 and Intermediate 38 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.06 (d, J = 6.6 Hz, 3H), 3.68 (s, 2H), 4.00-4.05 (m. 1H), 5.49 (d, J =5.1 Hz, 1H), 7.25-7.54 (m, 11H), 8.69 (s, 1H), 8.77 (s, 1H), 10.30 (s,1H). N-(4-(3-(2-Chloro-4- fluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example40

Intermediate 2 and Intermediate 39 Method B ¹H NMR (300 MHz, DMSO- d₆) δ0.85 (t, J = 6.9 Hz, 3H), 1.06 (d, J = 6.0 Hz, 3H), 2.27 (q, J = 6.9 Hz,2H), 3.67 (s, 2H), 4.03-4.07 (m, 1H), 5.49 (br s, 1H), 7.17-7.49 (m,12H), 8.66 (s, 1H), 8.72 (s, 1H), 10.27 (s, 1H); APCI- MS (m/z) 488 (M +H)⁺. 2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2- yl)phenyl)acetamide Example 41

Intermediate 2 and Intermediate 40 Method A ¹H NMR (300 MHz, CDCl₃) δ1.00 (t, J = 7.8 Hz, 3H), 2.08-2.21 (m, 3H), 2.65-2.71 (m, 6H), 3.33 (s,6H), 3.60- 3.64 (m, 2H), 3.80 (s, 2H), 7.43 (d, J = 8.4 Hz, 3H), 7.50(d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.86(d, J = 8.4 Hz, 2H),8.06 (s, 1H), 8.15 (s, 1H); APCI-MS (m/z) 510 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (4-(2-methoxyethyl)piperazin-1-yl)pyrazin-2- yl)phenyl)acetamide Example 42

Intermediate 2 and Intermediate 41 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J =7.5 Hz, 3H), 2.19-2.23 (m, 2H), 2.94-3.10 (m, 2H), 3.20-3.35(m, 9H), 3.73 (s, 2H), 3.74-3.84 (m, 2H), 7.47 (s, 4H), 7.72 (d, J = 7.8Hz, 2H), 7.88 (d, J = 7.8 Hz, 2H), 8.16 (d, J = 11.1 Hz, 2H), 10.38 (s,1H); APCI-MS (m/z) 508 (M + H)⁺. N-(4-(3-(4-Acetyl-2-methylpiperazin-1-yl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difiuoropropyl)phenyl)acetamide Example 43

Intermediate 2 and Intermediate 42 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.8 Hz, 3H), 2.07-2.22 (m, 2H), 3.77 (s, 2H), 7.34-7.41 (m,6H), 7.49 (d, J = 7.8 Hz, 2H), 8.66 (d, J = 4.8 Hz, 2H), 8.82 (s, 2H),9.15 (s, 1H); ESI-MS (m/z) 446 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (pyrimidin-5-yl)pyrazin-2-yl)phenyl)acetamide Example 44

Intermediate 2 and Intermediate 43 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.8 Hz, 3H), 1.91 (s, 3H), 2.16-2.18 (m, 2H), 3.69 (s, 2H),7.03-7.07 (m, 2H), 7.04-7.29 (m, 3H), 7.42-7.53 (m, 5H), 8.67 (s, 1H),8.72 (s, 1H), 10.30 (s, 1H); APCI-MS (m/z) 476 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (4-fluoro-2- methylphenyl)pyrazin-2-yl)phenyl)acetamide Example 45

Intermediate 2 and Intermediate 38 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 6.9 Hz, 3H), 2.16-2.22 (m, 2H), 3.69 (s, 2H), 7.28 (d, J =8.4 Hz, 2H), 7.30-7.60 (m, 9H), 8.69 (s, 1H), 8.77 (s, 1H), 10.31 (s,1H); APCI-MS (m/z) 496 (M + H)⁺. N-(4-(3-(2-Chloro-4-fluorophenyl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 46

Intermediate 2 and Intermediate 44 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.15-2.19 (m, 2H), 3.69 (s, 2H), 7.08-7.18 (m,4H), 7.36-7.53 (m, 9H), 8.54 (s, 1H), 8.60 (s, 1H), 10.24 (s, 1H);APCI-MS (m/z) 477 (M + H)⁺. N-(4-(3-(4- Chlorophenyl)pyridin-4-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 47

Intermediate 2 and Intermediate 45 Method A ¹H NMR (300 MHz, CDCl₃) δ0.99 (t, J = 7.2 Hz, 3H), 1.90 (s, 3H), 2.07-2.22 (m, 2H), 2.31 (s, 3H),3.73 (s, 2H), 6.94-7.01 (m, 2H), 7.06-7.12 (m, 2H), 7.34-7.39 (m, 5H),7.49 (d, J = 7.8 Hz, 2H), 8.56 (s, 1H), 8.59 (s, 1H); APCI-MS (m/z) 472(M + H)⁺. 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-(2,4-dimethylphenyl)pyrazin-2- yl)phenyl)acetamide Example 48

Intermediate 2 and Intermediate 46 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.8 Hz, 3H), 2.17-2.25 (m, 2H), 2.33 (s, 3H), 3.69 (s, 2H),6.91-6.97 (m, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H),7.43-7.55 (m, 7H), 8.70 (d, J = 9.3 Hz, 2H), 10.31 (s, 1H); APCI-MS(m/z) 476 (M + H)⁺. 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-(2-fluoro-4- methylphenyl)pyrazin-2- yl)phenyl)acetamide Example 49

Intermediate 2 and Intermediate 47 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.88 (t, J = 7.2 Hz, 3H), 2.15-2.39 (m, 2H), 3.67 (s, 2H), 6.56 (d, J =6.3 Hz, 1H), 7.24-7.30 (m, 4H), 7.40-7.50 (m, 6H), 7.70 (s, 1H), 8.11(d, J = 5.7 Hz, 1H), 10.33 (s, 1H); APCI- MS (m/z) 512 (M + H)⁺.N-(4-(1-(2-Chloro-4- fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)phenyl)- 2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 50

Intermediate 2 and Intermediate 48 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.8 Hz, 3H), 2.16-2.22 (m, 2H), 3.69 (s, 2H), 7.29 (d, J =8.1 Hz, 2H), 7.42-7.55 (m, 7H), 7.63 (s, 1H), 8.70 (s, 1H), 8.79 (s,1H), 10.32 (s, 1H): APCI- MS (m/z) 512 (M + H)⁺. N-(4-(3-(2,4-Dichlorophenyl)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 51

Intermediate 3 and Intermediate 45 Method B ¹H NMR (300 MHz, CDCl₃) δ1.23 (d, J = 5.7 Hz, 3H), 1.91 (s, 3H), 2.31 (s, 3H), 3.72 (s, 2H),4.13-4.17 (m, 1H), 6.95 (s, 1H), 6.99 (d, J = 6.9 Hz, 1H), 7 10 (d, J =7.8 Hz, 1H), 7.19 (s, 1H), 7.35-7.40 (m, 5H), 7.50 (d, J = 8 1 Hz, 2H),8.59 (d, J = 8.7 Hz, 2H); APCI-MS (m/z) 488 (M + H)⁺.2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(2,4-dimethylphenyl)pyrazin-2- yl)phenyl)acetamide Example 54

Intermediate 3 and Intermediate 49 Method B ¹H NMR (300 MHz, DMSO- d₆) δ0.63-0.70 (m, 4H), 1.07 (d, J = 6.3 Hz, 3H), 1.91- 1.95 (m, 1H),3.08-3.12 (m, 4H), 3.49-3.53 (m, 2H), 3.68-3.72 (m, 2H), 3.73 (s, 2H),4.02-4.06 (m, 1H), 5.47-5.51 (m, 1H), 7.44 (s, 4H), 7.73 (d, J = 8.4 Hz,2H), 7.90 (d, J = 7.2 Hz, 2H), 8.14 (s, 1H), 8.19 (s, 1H), 10.38 (s,1H); ESI-MS (m/z) 536 (M + H)⁺. N-(4-(3-(4-(Cyclopropanecarbonyl)piperazin- 1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example 55

Intermediate 2 and Intermediate 50 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.88 (t, J = 7.2 Hz, 3H), 2.15-2.21 (m, 2H), 3.27 (s, 3H), 3.68 (s, 2H),6.72-6.76 (m, 2H), 7.06 (d, J = 6.3 Hz, 2H), 7.42-7.55 (m, 8H),8.34-8.43 (m, 2H), 10.24 (s, 1H); APCI-MS (m/z) 507 (M + H)⁺.N-(4-(3-((4- Chlorophenyl)(methyl)amino) pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 56

Intermediate 2 and Intermediate 51 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.15-2.23 (m, 2H), 2.57 (s, 3H), 3.72 (s, 2H),4.42 (s, 2H), 7.12 (d, J = 6.9 Hz, 2H), 7.23-7.31 (m, 3H), 7.44-7.48 (m,4H), 7.70 (s, 4H), 8.08 (d, J = 6.3 Hz, 2H), 10.36 (s, 1H); APCI- MS(m/z) 487 (M + H)⁺. N-(4-(3- (Benzyl(methyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 57

Intermediate 2 and Intermediate 52 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.18-2.22 (m, 2H), 3.74 (s, 2H), 4.50 (s, 2H),6.90-6.95 (m, 1H), 7.25-7.32 (m, 5H), 7.44-7.48 (m, 4H), 7.64 (d, J =7.2 Hz, 2H), 7.68-7.74 (m, 3H), 7.89 (s, 1H), 10.39 (s, 1H); APCI-MS(m/z) 473 (M + H)⁺. N-(4-(3-(Benzylamino)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example 58

Intermediate 2 and Intermediate 53 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 2.18-2.23 (m, 2H),3.74 (s, 2H), 5.14-5.18 (m, 1H), 6.31-6.35 (m, 1H), 7.17 (d, J = 6.3 Hz,1H), 7.25-7.37 (m, 4H), 7.45-7.49 (m, 4H), 7.65 (d, J = 7.2 Hz, 2H),7.70- 7.75 (m, 3H), 7.86 (s, 1H), 10.40 (s, 1H); APCI-MS (m/z) 487 (M +H)⁺. 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-((1-phenylethyl)amino)pyrazin- 2-yl)phenyl)acetamide Example 59

Intermediate 2 and Intermediate 54 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J =7.8 Hz, 3H), 1.43 (d, J = 6.6 Hz, 3H), 2.18-2.25 (m, 2H),3.74 (s, 2H), 5.14-5.18 (m, 1H), 6.32- 6.36 (m, 1H), 7.17 (d, J = 7.2Hz, 1H), 7.27 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.45-7.49(m, 4H), 7.65 (d, J = 8.4 Hz, 2H), 7.72-7.78 (m, 3H), 7.86 (s, 1H),10.41 (s, 1H); APCI- MS (m/z) 487 (M + H)⁺. (R)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- ((1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 60

Intermediate 2 and Intermediate 55 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.87 (t, J = 7.5 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.13-2.17 (m, 2H),2.31 (s, 3H), 3.69 (s, 2H), 5.25-5.29 (m, 1H), 7.13(d, J = 7.2 Hz, 2H),7.18-7.27 (m, 3H), 7.41-7.45 (m, 4H), 7.65 (s, 4H), 8.05 (s, 2H), 10.32(s, 1H); APCI-MS (m/z) 501 (M + H)⁺. (R)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (methyl(1- phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 61

Intermediate 2 and Intermediate 56 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 2.16-2.25 (m, 2H),3.74 (s, 2H), 5.14-5.18 (m, 1H), 6.35 (d, J = 7.8 Hz, 1H), 7.17 (t, J =7.2 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H),7.45-7.49 (m, 4H), 7.65 (d, J = 9.0 Hz, 2H), 7.72-7.79 (m, 3H), 7.87 (s,1H), 10.41 (s, 1H): APCI- MS (m/z) 487 (M + H)⁺. (S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- ((1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 62

Intermediate 2 and Intermediate 57 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 1.43 (d, J = 6.3 Hz, 3H), 2.16-2.25 (m, 2H),2.33 (s, 3H), 3.72 (s, 2H), 5.29-5.35 (m, 1H), 7.16 (d, J = 7.2 Hz, 2H),7.22-7.29 (m, 3H)- 7.44-7.48 (m, 4H), 7.67 (s, 4H), 8.08 (s, 2H), 10.34(s, 1H); APCI-MS (m/z) 501 (M + H)⁺. (S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (methyl(1- phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 63

Intermediate 2 and Intermediate 58 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.5 Hz, 3H), 1.42 (d, J = 6.3 Hz, 3H), 2.17-2.31 (m, 2H),3.74 (s, 2H), 5.13 (t, J = 6.3 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 7.32(d, J= 7.8 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 7.45-7.49 (m, 4H), 7.65(d, J = 7.8 Hz, 2H), 7.72-7.78 (m, 3H), 7.85 (s, 1H), 10.42 (s, 1H);APCI- MS (m/z) 521 (M + H)⁺. (S)-N-(4-(3-((1-(4-Chlorophenyl)ethyl)amino)pyrazin- 2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 64

Intermediate 2 and Intermediate 59 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.43(d, J = 6.3 Hz, 3H), 2.18-2.32 (m, 2H),3.75 (s, 2H), 5.14 (t, J = 6.3 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 7.22(d, J = 7.8 Hz, 2H), 7.28- 7.35 (m, 2H), 7.42-7.50 (m, 4H), 7.67 (d, J =8.4 Hz, 2H), 7.73-7.79 (m, 3H), 7.86 (s, 1H), 10.42 (s, 1H); APCI- MS(m/z) 521 (M + H)⁺. (S)-N-(4-(3-((1-(3- Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example65

Intermediate 2 and Intermediate 60 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 1.43 (d, J = 6.3 Hz, 3H), 2.18-2.22 (m, 2H),2.32 (s, 3H), 3.72 (s, 2H), 5.26-5.31 (m, 1H), 7.19 (d, J = 7.8 Hz, 2H),7.34 (d, J = 8.4 Hz, 2H), 7.44-7.48 (m, 4H), 7.65-7.69 (m, 4H), 8.08 (d,J = 5.1 Hz, 2H), 10.35 (s, 1H). (S)-N-(4-(3-((1-(4-Chlorophenyl)ethyl)(methyl) amino)pyrazin-2-yl)phenyl)-2-(4- (1,1-difluoropropyl)phenyl)acetamide Example 66

Intermediate 2 and Intermediate 61 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 2.13-2.23 (m, 2H),3.75 (s, 2H), 5.39-5.43 (m, 1H), 6.57 (d, J = 7.5 Hz, 1H), 7.21- 7.25(m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 7.45-7.49 (m, 5H), 7.70-7.84 (m, 6H),10.42 (s, 1H); APCI-MS (m/z) 520 (M)⁺. (S)-N-(4-(3-((1-(2-Chlorophenyl)ethyl)amino)pyrazin- 2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 67

Intermediate 2 and Intermediate 62 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.36 (d, J = 6.3 Hz, 3H), 2.18-2.25 (m, 2H),2.40 (s, 3H), 3.74 (s, 2H), 5.21-5.25 (m, 1H), 6.44 (d, J = 6.3 Hz, 1H),6.92-7.01 (m, 2H), 7.39-7.50 (m, 5H), 7.63 (d, J = 8.4 Hz, 2H), 7.74 (d,J = 8.4 Hz, 3H), 7.86 (s, 1H), 10.42 (s, 1H). (S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- ((1-(4-fluoro-2-methylphenyl)ethyl)amino) pyrazin-2-yl)phenyl)acetamide Example 68

Intermediate 3 and Intermediate 61 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.9 Hz, 3H), 1.41 (d, J = 6.9 Hz, 3H), 3.74 (s, 2H), 4.06(br s, 1H), 5.39-5.43 (m, 1H), 6.57 (d, J = 6.9 Hz, 1H), 7.21- 7.26 (m,3H), 7.36-7.46 (m. 6H), 7.70 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz,2H), 7.84 (s, 1H), 10.42 (s, 1H); APCI-MS (m/z) 537 (M + H)⁺.N-(4-(3-(((S)-1-(2- Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoro-2-hydroxypropyl)phenyl)acetamide Example 69

Intermediate 2 and Intermediate 63 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.88 (t, J = 7.2 Hz, 3H), 1.34 (d, J = 5.7 Hz, 3H), 2.15-2.25 (m, 5H),2.32 (s, 3H), 3.73 (s, 2H), 5.21-5.25 (m, 1H), 6.24 (d, J = 6.3 Hz, 1H),6.88-6.90 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.45- 7.47 (m, 4H), 7.60(d, J = 7.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 3H), 7.85 (s, 1H), 10.39 (s,1H); APCI-MS (m/z) 513 (M − H)⁻. (S)-2-(4-(1,1-Difluoropropyl)pheny)-N-(4-(3- ((1-(2-4- dimethylphenyl)ethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 70

Intermediate 2 and Intermediate 64 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H), 2.18-2.25 (m, 2H),3.75 (s, 2H), 5.35-5.39 (m, 1H), 6.62-6.65 (m, 1H), 7.11-7.15 (m, 2H),7.35 (d, J = 8.7 Hz, 1H), 7.45-7.49 (m, 5H), 7.67-7.85 (m, 5H), 10.42(s, 1H); APCI-MS (m/z) 539 (M + H)⁺ (S)-N-(4-(3-((1-(2-Chloro-4-fluorophenyl)ethyl)amino) pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 71

Intermediate 3 and Intermediate 65 Method B ¹H NMR (300 MHz, DMSO- d₆) δ0.83-0.88 (m, 2H), 1.07 (d, J = 6.3 Hz, 3H), 1.11- 1.15 (m, 2H),1.62-1.72 (m, 5H), 2.99-3.13 (m, 2H), 3.10-3.15 (m, 3H), 3.73 (s, 2H),4.03 (br s, 1H), 5.52 (d, J = 5.7 Hz, 1H), 6.25 (br s, 1H), 7.42-7.46(m, 3H), 7.57 (d, J = 8.4 Hz, 2H), 7.69- 7.75 (m, 3H), 77.91 (s, 1H),10.39 (s, 1H). N-(4-(3- ((Cyclohexylmethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoro-2-hydroxypropyl)phenyl)acetamide Example 72

Intermediate 3 and Intermediate 58 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.9 Hz, 3H), 1.42 (d, J = 6.3 Hz, 3H), 3.74 (s, 2H), 4.05(br s, 1H), 5.11-5.15 (m, 1H), 5.49-5.53 (m, 1H), 6.49 (d, J = 7.5 Hz,1H), 7.32-7.40 (m, 7H), 7.65 (d, J = 8.4 Hz, 2H), 7.72-7.76 (m, 3H),7.82-7.86 (m, 2H), 10.41 (s, 1H). N-(4-(3-(((S)-1-(4-Chlorophenyl)ethyl)amino) pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoro-2-hydroxypropyl)phenyl)acetamide Example 73

Intermediate 3 and Intermediate 66 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.3 Hz, 3H), 1.42 (d, J = 6.6 Hz, 3H), 3.85 (s, 2H), 4.05(br s, 1H), 5.39-5.46 (m, 1H), 5.52 (d, J = 6.0 Hz, 1H), 683 (d, J = 6.9Hz, 1H), 7.18-7.25 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.45 (s, 4H),7.56-7.65 (m. 2H), 7.79 (s, 1H), 7.87 (s, 1H), 8.12 (t, J = 7.8 Hz, 2H),10.19 (s, 1H); ESI-MS (m/z) 555 (M + H)⁺. N-(4-(3-(((S)-1-(2-Chlorophenyl)ethyl)amino) pyrazin-2-yl)-2-fluorophenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example 74

Intermediate 3 and Intermediate 67 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.9 Hz, 3H), 1.37 (d, J = 6.6 Hz, 3H), 3.76 (s, 2H), 4.05(br s, 1H), 5.40-5.45 (m, 1H), 5.52 (d, J = 6.0 Hz, 1H), 6.62 (d, J =7.2 Hz, 1H), 7.18-7.25 (m, 3H), 7.37 (d, J =7.2 Hz, 1H), 7.45 (s, 6H),7.73-7.78 (m, 2H), 7.90 (s, 1H), 10.61 (s, 1H); ESI-MS (m/z) 555 (M +H)⁺. N-(4-(3-(((S)-1-(2- Chlorophenyl)ethyl)amino)pyrazin-2-yl)-3-fluorophenyl)-2-(4- (1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 75

Intermediate 2 and Intermediate 68 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.18-2.25 (m, 2H), 3.73 (s, 2H), 5.48 (s, 2H),6.01 (br s, 1H), 7.35-7.47 (m, 8H), 7.69 (d, J = 8.4 Hz, 2H), 8.03 (d, J= 8.7 Hz, 2H), 8.17 (s, 1H), 8.31 (s, 1H), 10.40 (s, 1H); APCI-MS (m/z)474 (M + H)⁺. N-(4-(3-(Benzyloxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 76

Intermediate 2 and Intermediate 69 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.63 (d, J = 6.3 Hz, 3H), 2.16-2.25 (m, 2H),3.75 (s, 2H), 6.21-6.26 (m, 1H), 7.30-7.35 (m, 3H), 7.40-7.50 (m, 6H),7.73 (d, J = 8.7 Hz, 2H), 8.06-8.12 (m, 3H), 8.25 (s, 1H), 10.43 (s,1H); APCI- MS (m/z) 488 (M + H)⁺. 2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (1-phenylethoxy)pyrazin-2-yl)phenyl)acetamide Example 77

Intermediate 2 and Intermediate 70 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.16-2.21 (m, 2H), 3.73 (s, 2H), 5.51 (s, 2H),7.24-7.27 (m, 1H), 7.44-7.48 (m, 4H), 7.55 (d, J = 8.7 Hz, 1H),7.65-7.70 (m, 3H), 8.00 (d, J = 9.0 Hz, 2H), 8.19 (s, 1H), 8.34 (s, 1H),10.39 (s, 1H); APCI-MS (m/z) 526 (M + H)⁺. N-(4-(3-((2-Chloro-4-fluorobenzyl)oxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 78

Intermediate 3 and Intermediate 68 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.06 (d, J = 6.9 Hz, 3H), 3.72 (s, 2H), 4.03 (br s, 1H), 5.46-5.60 (m,3H), 7.37-7.50 (m, 9H), 7.70 (d, J = 7.2 Hz, 2H), 8.03 (d, J = 8.4 Hz,2H), 8.17 (s, 1H), 8.32 (s, 1H), 10.39 (s, 1H); APCI-MS (m/z) 490 (M +H)⁺. N-(4-(3-(Benzyloxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 79

Intermediate 2 and Intermediate 71 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.63 (d, J = 6.3 Hz, 3H), 2.12-2.26 (m, 2H),3.75 (s, 2H), 6.24-6.28 (m, 1H), 7.24-7.49 (m, 9H), 7.73 (d, J = 8.4 Hz,2H), 8.05-8.09 (m, 3H), 8.25 (s, 1H), 10.44 (s, 1H); APCI-MS (m/z) 488(M + H)⁺. (R)-2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-(1-phenylethoxy)pyrazin-2- yl)phenyl)acetamide Example 80

Intermediate 2 and Intermediate 72 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.64 (d, J = 6.3 Hz, 3H), 2.16-2.25 (m, 2H),3.75 (s, 2H), 6.25-6.29 (m, 1H), 7.27-7.35 (m, 4H), 7.39-7.48 (m, 5H),7.73 (d, J = 8.7 Hz, 2H), 8.05-8.09 (m, 3H), 8.24 (s, 1H), 10.43 (s,1H); APCI- MS (m/z) 488 (M + H)⁺. (S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3- (1-phenylethoxy)pyrazin-2-yl)phenyl)acetamide Example 81

Intermediate 2 and Intermediate 73 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.88-0.93 (m, 5H), 1.20-1.25 (m, 1H), 1.66 (d, J = 6.6 Hz, 3H),2.14-2.18 (m, 4H), 3.75 (s, 2H), 6.73-6.77 (m, 1H), 7.01-7.05 (m, 1H),7.12-7.16 (m, 2H), 7.32-7.36 (m, 2H), 7.45-7.49 (m, 3H), 7.75 (d, J =8.7 Hz, 2H), 8.08-8.14 (m, 3H), 8.22 (s, 1H), 10.42 (s, 1H); APCI- MS(m/z) 528 (M + H)⁺. N-(4-(3-(1-(2- Cyclopropylphenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1- difluoropropyl)phenyl)acetamide Example82

Intermediate 3 and Intermediate 74 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.9 Hz, 3H), 1.39-1.46 (m, 4H), 3.74 (s, 2H), 4.03 (br s,1H), 5.51- 5.55 (m, 1H), 7.17 (d, J = 6.9 Hz, 2H), 7.25 (d, J = 6.9 Hz,2H), 7.45 (s, 5H), 7.75 (d, J = 8.7 Hz, 2H), 8.03- 8.08 (m, 3H), 8.26(s, 1H), 10.44 (s, 1H); APCI-MS (m/z) 516 (M + H)⁺.2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-1-phenylcyclopropoxy)pyrazin- 2-yl)phenyl)acetamide Example 83

Intermediate 2 and Intermediate 75 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.64 (d, J = 6.9 Hz, 3H), 2.18-2.23 (m, 2H),3.75 (s, 2H), 6.47-6.51 (m, 1H), 7.29-7.32 (m, 3H), 7.45-7.49 (m, 5H),7.74 (d, J = 8.7 Hz, 2H), 8.06-8.12 (m, 3H), 8.26 (s, 1H), 10.44 (s,1H); APCI- MS (m/z) 522 (M + H)⁺. (R)-N-(4-(3-(1-(2-Chlorophenyl)ethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 84

Intermediate 3 and Intermediate 75 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.9 Hz, 3H), 1.64 (d, J = 6.3 Hz, 3H), 3.75 (s, 2H), 4.04(br s, 1H), 5.52 (d, J = 5.7 Hz, 1H), 6.47-6.51 (m, 1H), 7.29-7.32 (m,3H), 7.45 (s, 5H), 7.75 (d, J = 8.7 Hz, 2H), 8.06-8.12 (m, 3H), 8.26 (s,1H), 10.44 (s, 1H); APCI- MS (m/z) 538 (M + H)⁺. N-(4-(3-((R)-1-(2-Chlorophenyl)ethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 85

Intermediate 2 and Intermediate 76 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 1.64 (d, J = 6.3 Hz, 3H), 2.12-2.27 (m, 2H),3.75 (s, 2H), 6.46-6.52 (m, 1H), 7.27-7.32 (m, 3H), 7.42-7.45 (m, 5H),7.74(d, J = 5.7 Hz, 2H), 8.07-8.12 (m, 3H), 8.26 (s, 1H), 10.45 (s, 1H);APCI- MS (m/z) 520 (M − H)⁻. (S)-N-(4-(3-(1-(2-Chlorophenyl)ethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 86

Intermediate 3 and Intermediate 76 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.3 Hz, 3H), 1.64 (d, J = 6.9 Hz, 3H), 3.75 (s, 2H), 4.05(br s, 1H), 5.52 (d, J = 6.3 Hz, 1H), 6.47-6.51 (m, 1H), 7.29-7.32 (m,3H), 7.45 (s, 5H), 7.75 (d, J = 9.0 Hz, 2H), 8.07-8.12 (m, 3H), 8.27 (s,1H), 10.45 (s, 1H); APCI- MS (m/z) 538 (M + H)⁺. N-(4-(3-((S)-1-(2-Chlorophenyl)ethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 87

Intermediate 2 and Intermediate 77 Method A ¹H NMR (300 MHz, DMSO- d₆) δ1.89 (t, J = 7.2 Hz, 3H), 2.16-2.21 (m, 2H), 3.75 (s, 2H), 7.28-7.35 (m,2H), 7.43- 7.47 (m, 5H), 7.62 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.7 Hz,2H), 8.06-8.16 (m, 3H), 8.46 (s, 1H), 10.47 (s, 1H); ESI-MS (m/z) 494(M + H)⁺. N-(4-(3-(2- Chlorophenoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide Example 88

Intermediate 3 and Intermediate 78 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.6 Hz, 3H), 1.62 (d, J = 6.3 Hz, 3H), 2.25 (s, 3H), 3.74(s, 2H), 4.04 (br s, 1H), 5.52 (d, J = 5.7 Hz, 1H), 6.43-6.47 (m, 1H),7.10 (d, J = 7.8 Hz, 1H), 7.27-7.34 (m, 2H), 7.45 (s, 4H), 7.74 (d, J =9.0 Hz, 2H), 8.05-8.11 (m, 3H), 8.24 (s, 1H), 10.44 (s, 1H); APCI- MS(m/z) 553 (M + H)⁺. N-(4-(3-((R)-1-(2-Chloro-4-methylphenyl)ethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 89

Intermediate 2 and Intermediate 79 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.89 (t, J = 7.2 Hz, 3H), 2.11-2.19 (m, 2H), 2.21 (s, 3H), 2.43 (s, 3H),3.73 (s, 2H), 5.29 (s, 2H), 7.43-7.48 (m, 4H), 7,68 (d, J = 8.7 Hz, 2H),7.95 (d, J = 8.7 Hz, 2H), 8.19 (s, 1H), 8.31 (s, 1H), 10.40 (s, 1H);ESI-MS (m/z) 493 (M + H)⁺. 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-((3,5-dimethylisoxazol-4- yl)methoxy)pyrazin-2- yl)phenyl)acetamideExample 90

Intermediate 3 and Intermediate 80 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 5.7 Hz, 3H), 2.12 (s, 3H), 2.21 (s, 3H), 2.84 (t, J = 6.3Hz, 2H), 3.74 (s, 2H), 4.04 (br s, 1H), 4.48 (d, J = 6.3 Hz, 2H), 5.51(d, J = 6.0 Hz, 1H), 7.44 (s, 4H), 7.69 (d, J = 8.4 Hz, 2H), 7.89 (d, J= 8.1 Hz, 2H), 8.14 (s, 1H), 8.27 (s, 1H), 10.41 (s, 1H); ESI-MS (m/z)523 (M + H)⁺. 2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(2-(3,5-dimethylisoxazol-4- yl)ethoxy)pyrazin-2- yl)phenyl)acetamideExample 91

Intermediate 3 and Intermediate 81 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.04 (d, J = 6.3 Hz, 3H), 3.70 (s, 2H), 4.00 (br s, 1H), 5.53 (s, 2H),7.36-7.42 (m, 6H), 7.50-7.54 (m, 2H), 7.66 (d, J = 8.1 Hz, 2H), 8.00 (d,J = 8.4 Hz, 2H), 8.17(s, 1H), 8.31 (s, 1H), 10.38 (s, 1H); APCI-MS (m/z)524 (M + H)⁺. N-(4-(3-((2- Chlorobenzyl)oxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2- hydroxypropyl)phenyl)acetamide Example92

Intermediate 3 and Intermediate 82 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.0 Hz, 3H), 2.30 (s, 3H), 3.32 (s, 2H), 3.74 (s, 2H), 4.05(br s, 1H), 4.57 (br s, 2H), 5.52 (d, J = 6.0 Hz, 1H), 7.44 (s, 4H),7.67 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 8.14 (s, 1H), 8.28(s, 1H), 8.84 (s, 1H), 10.41 (s, 1H); ESI-MS (m/z) 525 (M + H)⁺.2-(4-(1,1-Difluoro-2- hydroxypropyl)phenyl)-N-(4-(3-(2-(4-methylthiazol-5- yl)ethoxy)pyrazin-2- yl)phenyl)acetamide Example93

Intermediate 3 and Intermediate 83 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.6 Hz, 3H), 1.18-1.45 (m, 6H), 1 72-1.82 (m, 5H), 3.73 (s,2H), 4.06 (br s, 1H), 4.19 (d. J = 6.0 Hz, 2H), 5.49 (d, J = 6.0 Hz,1H), 7.44 (s, 4H), 7.71 (d, J = 9.0 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H),8.12 (m, 1H), 8.26 (s, 1H), 10.39 (s, 1H); ESI-MS (m/z) 496 (M + H)⁺.N-(4-(3- (Cyclohexylmethoxy)pyrazin-2- yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 94

Intermediate 3 and Intermediate 84 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 5.7 Hz, 3H), 3.50-3.55 (m, 2H), 3.73 (s, 2H), 3.84-3.88 (m,2H), 4.05 (br s, 1H), 4.30-4.35 (m, 1H), 4.36 (s, 2H), 5.47-5.51 (m,1H), 7.26-7.30 (m, 5H), 7.45 (s, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.69 (d,J = 8.4 Hz, 2H), 8.02 (s, 1H), 8.07 (s, 1H), 10.37 (s, 1H); ESI-MS (m/z)543 (M − H)⁻. N-(4-(3-(3-(Benzyloxy)azetidin-1-yl)pyrazin-2-yl)phenyl)-2-(4- (1,1-difluoro-2-hydroxypropyl)phenyl)acetamide Example 95

Intermediate 3 and Intermediate 63 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.6 Hz, 3H), 1.36 (d, J = 6.9 Hz, 3H), 2.19 (s, 3H), 2.19(s, 3H), 3.74 (s, 2H), 4.08 (br s, 1H), 5.23-5.27 (m, 1H), 5.48-5.52 (m,1H), 6.20-6.24 (m, 1H), 6.89-6.93 (m, 2H), 7.21-7.26 (m, 2H), 7.45 (s,4H), 7.62 (d, J = 9.0 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.87 (s, 1H),10.39 (s, 1H); APCI-MS (m/z) 531 (M + H)⁺. 2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3- (((S)-1-(2,4- dimethylphenyl)ethyl)amino)pyrazin-2-yl)phenyl)acetamide Example 96

Intermediate 2 and Intermediate 49 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.66-0.76 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H), 1.91-1.95 (m, 1H),2.19-2.46 (m, 2H), 3.08-3.12 (m, 4H), 3.48-3.52 (m, 2H), 3.65-3.72 (m,2H), 3.74 (s, 2H), 7.47 (s, 4H), 7.73 (d, J = 8.4 Hz, 2H), 7.90 (d, J =9.0 Hz, 2H), 8.15 (s, 1H), 8.20 (s, 1H), 10.39 (s, 1H). N-(4-(3-(4-(Cyclopropanecarbony)piperazin- 1-yl)pyrazin-2-yl)phenyl)-2-(4- (1,1-difluoropropyl)phenyl)acetamide Example 97

Intermediate 2 and Intermediate 85 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.2 Hz, 3H), 2.14-2.25 (m, 2H), 3.34-3.38 (m, 1H),3.56-3.61 (m, 1H), 3.74 (s, 2H), 4.83 (br s, 1H), 5.52 (br s, 1H), 6.02(d, J = 4.8 Hz, 1H), 7.25-7.35 (m, 6H), 7.47 (s, 3H), 7.53 (d, J = 8.7Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.96 (s, 1H), 10.39 (s,1H). 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3- ((2-hydroxy-1-phenylethyl)amino)pyrazin-2- yl)phenyl)acetamide Example 98

Intermediate 3 and Intermediate 86 Method B ¹H NMR (300 MHz, DMSO- d₆) δ1.07 (d, J = 6.3 Hz, 3H), 1.59 (d, J = 6.3 Hz, 3H), 2.20 (s, 3H), 2.34(s, 3H), 3.56 (s, 1H), 3.74 (s, 2H), 4.04 (br s, 1H), 5.50 (d, J = 6.3Hz, 1H), 6.35 (d, J = 6.9 Hz, 1H), 6.91-6.98 (m, 2H), 7.23 (d, J = 7.8Hz, 1H), 7.45 (s, 4H), 7.73 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 8.1 Hz,2H), 8.22 (s, 1H), 10.41 (s, 1H). 2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3- ((R)-1-(2,4-dimethylphenyl)ethoxy)pyrazin- 2-yl)phenyl)acetamide Example 99

Intermediate 2 and Intermediate 87 Method A ¹H NMR (300 MHz, DMSO- d₆) δ0.90 (t, J = 7.5 Hz, 3H), 2.18-2.28 (m, 6H), 3.08-3.12 (m, 4H),3.34-3.44 (m, 1H), 3.73 (s, 2H), 4.39 (t, J = 6.3 Hz, 2H), 4.50 (t, J =6.3 Hz, 2H), 7.46-7.50 (m, 4H), 7.70 (d, J = 8.7 Hz, 2H), 7.85 (d, J =8.1 Hz, 2H), 8.12 (s, 1H), 8.16 (s, 1H), 10.37 (s, 1H); APCI-MS (m/z)508 (M + H)⁺. 2-(4-(1,1- Difluoropropyl)phenyl)-N-(4-(3-(4-(oxetan-3-yl)piperazin-1- yl)pyrazin-2- yl)phenyl)acetamide

Pharmacological Activity Biological Assay

The compounds described herein were screened for ROR gamma modulatoractivity using the TR-FRET assay (LanthaScreen™ available fromInvitrogen of Carlsbad, Calif.) as described in JBC 2011, 286, 26:22707-10; and Drug Metabolism and Disposition 2009, 37, 10: 2069-78.

TR-FRET Assay for ROR Gamma

The assay is based on the principle that binding of the agonist to theROR gamma causes a conformational change around helix 12 in the ligandbinding domain, resulting in higher affinity for the co-activatorpeptide. ROR gamma being constitutively active, the Fluorescein-D22co-activator peptide used in the assay is recruited in the absence of aligand. Binding of the co-activator peptide, causes an increase in theTR-FRET signal while binding of an antagonist decreases the recruitmentof the co-activator peptide, causing a decrease in the TR-FRET signalcompared to control with no compound. The assay was performed using atwo-step procedure, pre-incubation step with the compound followed bythe detection step on addition of the anti-GST tagged terbium (Tb) andfluorescein tagged fluorophores as the acceptor.

Test compounds or reference compounds such as T0901317 (Calbiochem) weredissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutionsand diluted to the desired concentration. The final concentration ofDMSO in the reaction was 4% (v/v). The assay mixture was prepared bymixing 10 nM of the GST-tagged ROR gamma ligand binding domain (LBD) inthe assay buffer containing 25 mM HEPES (pH 7.4), 100 mM NaCl, 5 mM DTTand 0.01% BSA with or without the desired concentration of the compound.The reaction was incubated at 22° C. for 1 hour. The pre-incubation stepwas terminated by addition of the detection mixture containing 300 nMFluorescein-D22 co-activator peptide and 10 nM lantha screen Tb-anti GSTantibody into the reaction mixture. After shaking for 5 minutes thereaction was further incubated for 1 hour at room temperature and readat 4° C. on an Infinite F500 reader as per the kit instructions(Invitrogen). The inhibition of test compound was calculated based onthe TR-FRET ratio of 520/495. The activity was calculated as a percentof control reaction. IC₅₀ values were calculated from dose responsecurve by nonlinear regression analysis using GraphPad Prism software.

The compounds prepared were tested using the above assay procedure andthe results obtained are given in Table 1. Percentage inhibition atconcentrations of 1.0 μM and 10.0 μM are given in the table along withIC₅₀ (nM) details for selected examples. The compounds were found tohave IC₅₀ less than 500 nM, preferably less than 100 nM, more preferablyless than 50 nM.

The IC₅₀ (nM) values are set forth in Table 1 wherein “A” refers to anIC₅₀ value of less than 50 nM; “B” refers to IC₅₀ value in range of50.01 to 100.0 nM; “C” refers to IC₅₀ values more than 100.01 to 500.0nM and “D” refers to IC₅₀ values more than 500 nM.

TABLE 2 In-vitro screening results % Inhibition at S. N. Example No. 1μM 10 μM IC₅₀ range 1. Example 1 80.93 81.51 A 2. Example 2 76.07 82.71A 3. Example 3 73.97 84.76 B 4. Example 4 60.73 77.81 D 5. Example 581.48 84.41 A 6. Example 6 87.42 86.39 A 7. Example 7 82.98 86.21 A 8.Example 8 73.56 85.3 C 9. Example 9 55.24 72.12 D 10. Example 10 78.1682.96 B 11. Example 11 78.76 83.8 A 12. Example 12 85.57 83.01 A 13.Example 13 82.69 84.39 A 14. Example 14 74.44 83.84 C 15. Example 1572.19 80.64 C 16. Example 16 69.91 60.55 — 17. Example 17 60.46 74.44 —18. Example 18 32.41 71.16 — 19. Example 19 42.16 48.79 — 20. Example 2065.47 78.01 — 21. Example 21 37.41 38.32 — 22. Example 22 46.68 56.2 —23. Example 23 36.56 68.59 — 24. Example 24 61.61 83.62 — 25. Example 2518.89 59.74 — 26. Example 26 71.91 79.57 C 27. Example 27 78.57 83.46 A28. Example 28 73.7 77.57 C 29. Example 29 77.07 79.83 A 30. Example 3081.32 82.48 A 31. Example 31 77.74 81.65 A 32. Example 32 15.29 65.07 —33. Example 33 27.32 75.76 — 34. Example 34 57.91 66.83 — 35. Example 3572.79 73.32 C 36. Example 36 2.6 8.3 — 37. Example 37 71.1 73.5 A 38.Example 38 70.7 74.9 C 39. Example 39 65.5 72.8 — 40. Example 40 71.476.9 A 41. Example 41 4.2 48.7 — 42. Example 42 51.9 76.1 — 43. Example43 12.21 33.58 — 44. Example 44 76.87 84.14 A 45. Example 45 81.09 80.8A 46. Example 46 69.96 77.08 — 47. Example 47 82.32 82.33 A 48. Example48 79.22 84.07 A 49. Example 49 83.95 88.78 A 50. Example 50 83.15 82.98A 51. Example 51 73.23 81.03 A 52. Example 52 78.62 84 A 53. Example 5370.49 77.01 A 54. Example 54 23.1 42.4 — 55. Example 55 56.5 64.6 — 56.Example 56 73.44 85.81 C 57. Example 57 69.4 85.2 — 58. Example 58 80.390.7 C 59. Example 59 58.65 79.73 — 60. Example 60 69.57 82.97 C 61.Example 61 84.15 91.38 B 62. Example 62 65.6 84.79 — 63. Example 6386.85 91.23 B 64. Example 64 76.23 84.93 C 65. Example 65 76.06 83.2 C66. Example 66 88.41 90.15 A 67. Example 67 87.89 92.37 A 68. Example 6893.52 96.9 A 69. Example 69 97.05 97.09 A 70. Example 70 94.1 93.75 A71. Example 71 20.49 73.7 — 72. Example 72 86.9 93.39 A 73. Example 7378.51 89.22 C 74. Example 74 79.25 89.87 B 75. Example 75 75.7 84.25 B76. Example 76 78.06 87.5 C 77. Example 77 80.49 73.7 A 78. Example 7889.59 93.87 A 79. Example 79 69.54 85.85 C 80. Example 80 69.47 86.27 C81. Example 81 83.18 88.3 C 82. Example 82 37.88 80.06 — 83. Example 8379.67 78.18 B 84. Example 84 83.77 81.93 B 85. Example 85 74.77 79.6 C86. Example 86 84.51 86.05 B 87. Example 87 16.28 32.43 — 88. Example 8887.37 85.55 A 89. Example 89 58.75 74.57 — 90. Example 90 90.71 93.86 A91. Example 91 79.34 82.61 A 92. Example 92 83.54 88.04 B 93. Example 9386.56 94.07 C 94. Example 94 15.85 45.59 — 95. Example 95 93.66 95.43 A96. Example 96 47.68 77.2 — 97. Example 97 22.5 46.22 — 98. Example 9889.55 89.01 A 99. Example 99 79.16 91.88 B (—): Not determined

1-56. (canceled)
 57. A compound of formula (I)

or a tautomer thereof, stereoisomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein Ring A is selected from

Ring B is selected from C₃₋₆cycloalkyl, C₆₋₁₄aryl, 3-15 memberedheterocyclyl and 5 to 14 membered heteroaryl; L is absent or is_(y)*-X—(CR^(x)R^(y))_(t)-*_(z); X is selected from O, NR^(x1) and

each of x, y and z represents a point of attachment; R¹ is selected fromhydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy; each occurrence of R² isindependently selected from cyano, halogen, hydroxyl, C₁₋₈alkyl,C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl, haloC₁₋₈alkoxy,hydroxyC₁₋₈alkyl, C(O)C₁₋₈alkyl, C₃₋₆cycloalkyl, C(O)C₃₋₆cycloalkyl and3 to 15 membered heterocyclic ring; each occurrence of R³ isindependently selected from halogen, cyano, C₁₋₈alkyl; haloC₁₋₈alkyl andC₃₋₆cycloalkyl; each occurrence of R⁴ is independently selected fromhalogen, cyano, C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl; eachoccurrence of R⁵ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl; R^(a) and R^(b), which maybe the same or different, are each independently selected from hydrogenand C₁₋₈alkyl; R^(x) and R^(y) which may be the same or different, areeach independently selected from hydrogen, C₁₋₈alkyl andhydroxyC₁₋₈alkyl; or R^(x) and R^(y) together with the carbon atom towhich they are attached, form a 3 to 6 membered cycloalkyl ring; R^(x1)is selected from hydrogen or C₁₋₈alkyl; ‘n’ is 0, 1, 2 or 3; ‘m’ is 0, 1or 2; ‘p’ is 0, 1 or 2; ‘q’ is 0, 1, 2 or 3 and ‘t’ is 0, 1, 2 or
 3. 58.The compound according to claim 57, wherein ring B is cyclohexyl,phenyl, 6-oxo-1,6-dihydropyridinyl, piperidinyl, piperazinyl,morpholinyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl or pyrimidinyl.59. The compound according to claim 57, wherein L is absent.
 60. Thecompound according to claim 57, wherein L is


61. The compound according to claim 57, wherein R¹ is hydroxyl, methylor methoxy.
 62. The compound according to claim 57, wherein ‘n’ is 0.63. The compound according to claim 57, wherein each R² is independentlycyano, F, Cl, methyl, ethyl, methoxy, methoxyethyl, trifluoromethyl,cyclopropyl, C(O)methyl, C(O)cyclopropyl or oxetan-3-yl and ‘n’ is 1 or2.
 64. The compound according to claim 57, wherein ‘m’ is
 0. 65. Thecompound according to claim 57, wherein R³ is methyl, tert-butyl ortrifluoromethyl and ‘m’ is
 1. 66. The compound according to claim 57,wherein ‘p’ is
 0. 67. The compound according to claim 57, wherein one ofR^(a) and R^(b) is hydrogen and the other is hydrogen or methyl.
 68. Thecompound according to claim 57, wherein R¹ is methyl; R^(a) is hydrogenand R^(b) is hydrogen.
 69. The compound according to claim 57, whereinR¹ is hydroxyl; R^(a) is hydrogen and R^(b) is methyl.
 70. The compoundaccording to claim 57, wherein


71. The compound according to claim 57, wherein

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2-cyclopropylphenyl, 2,4-dichlorophenyl,2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl,2-chloro-4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,3,5-dimethylisoxazol-4-yl, 1-methyl-1H-pyrazol-4-yl,4-methylthiazol-5-yl, pyridin-4-yl or pyrimidin-5-yl.
 72. The compoundaccording to claim 57, wherein Ring A is

Ring B is cyclohexyl, phenyl, 6-oxo-1,6-dihydropyridinyl, piperidinyl,piperazinyl, morpholinyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl orpyrimidinyl; L is absent or is

R¹ is hydroxyl, methyl or methoxy; R² is cyano, F, Cl, methyl, ethyl,methoxy, methoxyethyl, trifluoromethyl, cyclopropyl, C(O)methyl,C(O)cyclopropyl or oxetan-3-yl; R³ is methyl, tert-butyl ortrifluoromethyl; R⁴ is F; R^(a) is hydrogen; R^(b) is hydrogen ormethyl; ‘n’ is 0, 1 or 2; ‘m’ is 0 or 1; ‘p’ is 0 or 1; and ‘q’ is 0.73. The compound according to claim 57, wherein

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2-cyclopropylphenyl, 2,4-dichlorophenyl,2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl,2-chloro-4-methylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,3,5-dimethylisoxazol-4-yl, 1-methyl-1H-pyrazol-4-yl,4-methylthiazol-5-yl, pyridin-4-yl or pyrimidin-5-yl; L is absent or is

R¹ is hydroxyl, methyl or methoxy; R⁴ is F; R^(a) is hydrogen; R^(b) ishydrogen or methyl; ‘p’ is 0 or 1; and ‘q’ is
 0. 74. The compoundaccording to claim 57, represented by formula (II)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein Ring A is selected from

Ring B is selected from C₃₋₆cycloalkyl, C₆₋₁₄aryl, 3-15 memberedheterocyclyl and 5 to 14 membered heteroaryl; each of x and y representspoint of attachment; R¹ is selected from hydroxyl, C₁₋₈alkyl andC₁₋₈alkoxy; each occurrence of R² is independently selected from cyano,halogen, hydroxyl, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl,haloC₁₋₈alkyl, haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C(O)C₁₋₈alkyl,C₃₋₆cycloalkyl, C(O)C₃₋₆cycloalkyl and 3 to 15 membered heterocyclicring; each occurrence of R³ is independently selected from halogen,cyano, C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl; each occurrence ofR⁴ is independently selected from halogen, cyano, C₁₋₈alkyl;haloC₁₋₈alkyl and C₃₋₆cycloalkyl; R^(a) and R^(b), which may be same ordifferent, are each independently selected from hydrogen and C₁₋₈alkyl;‘n’ is 0, 1, 2 or 3; ‘m’ is 0, 1 or 2; and ‘p’ is 0, 1 or
 2. 75. Thecompound according to claim 74, wherein

is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-cyanophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl,4-chloro-2-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl,2,4-dimethylphenyl, 2-ethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 4-methoxyphenyl,4-(trifluoromethyl)phenyl, o-tolyl, p-tolyl, 4-acetylpiperazin-1-yl,4-acetyl-2-methylpiperazin-1-yl, 4-(cyclopropanecarbonyl)piperazin-1-yl,4,4-difluoropiperidin-1-yl, 4-ethylpiperazin-1-yl,4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl, 4-(oxetan-3-yl)piperazin-1-yl,morpholin-4-yl, (2S,6R)-2,6-dimethylmorpholin-4-yl,1-methyl-1H-pyrazol-4-yl, pyridin-4-yl or pyrimidin-5-yl; R¹ ishydroxyl, methyl or methoxy; R⁴ is F; R^(a) is hydrogen; R^(b) ishydrogen or methyl; and ‘p’ is 0 or
 1. 76. The compound according toclaim 57, represented by formula (III)

or a tautomer thereof, stereoisomer thereof or pharmaceuticallyacceptable salt thereof, wherein Ring B is selected from C₃₋₆cycloalkyl,C₆₋₁₄aryl, 3-15 membered heterocyclyl and 5 to 14 membered heteroaryl; Xis selected from —O—, —NR^(x1)— and

R¹ is selected from hydroxyl, C₁₋₈alkyl and C₁₋₈alkoxy; each occurrenceof R² is independently selected from cyano, halogen, hydroxyl,C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxyC₁₋₈alkyl, haloC₁₋₈alkyl,haloC₁₋₈alkoxy, hydroxyC₁₋₈alkyl, C(O)C₁₋₈alkyl, C₃₋₆cycloalkyl,C(O)C₃₋₆cycloalkyl and 3 to 15 membered heterocyclic ring; eachoccurrence of R⁴ is independently selected from halogen, cyano,C₁₋₈alkyl; haloC₁₋₈alkyl and C₃₋₆cycloalkyl; R^(a) and R^(b), which maybe same or different, are each independently selected from hydrogen andC₁₋₈alkyl; R^(x) and R^(y) which may be same or different, are eachindependently selected from hydrogen, C₁₋₈alkyl and hydroxyC₁₋₈alkyl; orR^(x) and R^(y) together with the carbon atom to which they areattached, form a 3 to 6 membered cycloalkyl ring; R^(x1) is selectedfrom hydrogen or C₁₋₈alkyl; ‘n’ is 0, 1, 2 or 3; ‘p’ is 0, 1 or 2; and‘t’ is 0, 1, 2 or
 3. 77. The compound according to claim 76, wherein

is cyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-cyclopropylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methylphenyl,2,4-dimethylphenyl, 4-fluoro-2-methylphenyl, 3,5-dimethylisoxazol-4-ylor 4-methylthiazol-5-yl;

y and z represents point of attachment; R¹ is hydroxyl, methyl ormethoxy; R⁴ is F; R^(a) is hydrogen; R^(b) is hydrogen or methyl; and‘p’ is 0 or
 1. 78. The compound according to claim 57, selected fromN-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-methoxyethyl)phenyl)acetamide;N-(4-(3-(3-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(2-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(4-Chloro-2-fluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(4-Chlorophenyl)pyridin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(4-fluorophenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(3,4-difluorophenyl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(2,4-Difluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(2-fluorophenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(p-tolyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-fluorophenyl)pyridin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-phenylpyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-Cyanophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(pyridin-4-yl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-morpholinopyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(5-(4-fluorophenyl)-3-methyl-H-pyrazol-1-yl)phenyl)acetamide;N-(4-(1-(tert-Butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(1-(tert-Butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-Acetylpiperazin-1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-Chlorophenyl)pyrazin-2-yl)-2-fluorophenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-methoxyphenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1,1-Difluoropropyl)phenyl)-N-(4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide;N-(4-(5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(2-Chlorophenyl)pyridin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(o-tolyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-methylpiperazin-1-yl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-ethylpiperazin-1-yl)pyrazin-2-yl)phenyl)acetamide;N-(4-(2-(4-Chlorophenyl)pyridin-3-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(4-(4-Chlorophenyl)pyridin-3-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(2-Chlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(5-(2,4-Dichlorophenyl)-3-methyl-1H-pyrazol-1-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(2-Chloro-4-fluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-(2-methoxyethyl)piperazin-1-yl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-Acetyl-2-methylpiperazin-1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(pyrimidin-5-yl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-fluoro-2-methylphenyl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(2-Chloro-4-fluorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(4-Chlorophenyl)pyridin-4-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(2,4-dimethylphenyl)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(2-fluoro-4-methylphenyl)pyrazin-2-yl)phenyl)acetamide;N-(4-(1-(2-Chloro-4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(2,4-Dichlorophenyl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2,4-dimethylphenyl)pyrazin-2-yl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide;(R)-2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-(Cyclopropanecarbonyl)piperazin-1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-((4-Chlorophenyl)(methyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(Benzyl(methyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(Benzylamino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;(R)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;(R)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(methyl(1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(methyl(1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;(S)—N-(4-(3-((1-(4-Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;(S)—N-(4-(3-((1-(3-Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;(S)—N-(4-(3-((1-(4-Chlorophenyl)ethyl)(methyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;(S)—N-(4-(3-((1-(2-Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((1-(4-fluoro-2-methylphenyl)ethyl)amino)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(((S)-1-(2-Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((1-(2,4-dimethylphenyl)ethyl)amino)pyrazin-2-yl)phenyl)acetamide;(S)—N-(4-(3-((1-(2-Chloro-4-fluorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-((Cyclohexylmethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(((S)-1-(4-Chlorophenyl)ethyl)amino)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(((S)-1-(2-Chlorophenyl)ethyl)amino)pyrazin-2-yl)-2-fluorophenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(((S)-1-(2-Chlorophenyl)ethyl)amino)pyrazin-2-yl)-3-fluorophenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(Benzyloxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(1-phenylethoxy)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-((2-Chloro-4-fluorobenzyl)oxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-(Benzyloxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;(R)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(1-phenylethoxy)pyrazin-2-yl)phenyl)acetamide;(S)-2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(1-phenylethoxy)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(1-(2-Cyclopropylphenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(1-phenylcyclopropoxy)pyrazin-2-yl)phenyl)acetamide;(R)—N-(4-(3-(1-(2-Chlorophenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-((R)-1-(2-Chlorophenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;(S)—N-(4-(3-(1-(2-Chlorophenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-((S)-1-(2-Chlorophenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(2-Chlorophenoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;N-(4-(3-((R)-1-(2-Chloro-4-methylphenyl)ethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((3,5-dimethylisoxazol-4-yl)methoxy)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-((2-Chlorobenzyl)oxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-(4-methylthiazol-5-yl)ethoxy)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(Cyclohexylmethoxy)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;N-(4-(3-(3-(Benzyloxy)azetidin-1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(((S)-1-(2,4-dimethylphenyl)ethyl)amino)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(4-(Cyclopropanecarbonyl)piperazin-1-yl)pyrazin-2-yl)phenyl)-2-(4-(1,1-difluoropropyl)phenyl)acetamide;2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-((2-hydroxy-1-phenylethyl)amino)pyrazin-2-yl)phenyl)acetamide;2-(4-(1,1-Difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-((R)-1-(2,4-dimethylphenyl)ethoxy)pyrazin-2-yl)phenyl)acetamideor2-(4-(1,1-Difluoropropyl)phenyl)-N-(4-(3-(4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-yl)phenyl)acetamideand pharmaceutically acceptable salts thereof.
 79. A compound of formula

or a stereoisomer thereof, or a pharmaceutically acceptable saltthereof.
 80. The compound according to claim 79, having formula

or a pharmaceutically acceptable salt thereof.
 81. The compoundaccording to claim 79, having formula

or a pharmaceutically acceptable salt thereof.
 82. A pharmaceuticalcomposition comprising a compound according to claim 57 and apharmaceutically acceptable excipient.
 83. The pharmaceuticalcomposition according to claim 82, wherein the pharmaceuticallyacceptable excipient is a carrier or diluent.
 84. A method of treating aRORγt mediated disease, disorder, syndrome, or condition in a subjectcomprising administering an effective amount of a compound according toclaim
 57. 85. The method according to claim 84, wherein the disease,disorder, syndrome or condition is an inflammatory or autoimmunedisease.
 86. The method according to claim 85, wherein the inflammatoryor autoimmune disease is selected from the group consisting ofrheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease(COPD), asthma, multiple sclerosis, colitis, ulcerative colitis andinflammatory bowel disease.
 87. The method according to claim 84,wherein the disease, disorder, syndrome or condition is pain, chronicpain, acute pain, inflammatory pain, arthritic pain, neuropathic pain,post-operative pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, cancer pain, pain due to burns,migraine or cluster headaches, nerve injury, neuritis, neuralgias,poisoning, ischemic injury, interstitial cystitis, viral, parasitic orbacterial infection, post-traumatic injury, or pain associated withirritable bowel syndrome.
 88. The method according to claim 84, whereinthe disease, disorder, syndrome or condition is chronic obstructivepulmonary disease (COPD), asthma, bronchospasm or cough.
 89. A method oftreatment of disease, disorder, syndrome or condition selected from thegroup consisting of chronic obstructive pulmonary disease (COPD),asthma, cough, pain, inflammatory pain, chronic pain, acute pain,arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis,colitis, ulcerative colitis, psoriasis and inflammatory bowel diseasecomprising administering to a subject in need thereof a compoundaccording to claim 57.